Cancer and immunomodulators in inflammatory bowel diseases.

CLINICAL REVIEW ARTICLE

Cancer and Immunomodulators in Inflammatory Bowel Diseases Livia Biancone, MD, PhD, Sara Onali, MD, PhD, Carmelina Petruzziello, MD, PhD, Emma Calabrese, MD, PhD, and Francesco Pallone, MD

Abstract: The widespread use of thiopurines and anti-tumor necrosis factors (TNFs) in inflammatory bowel disease (IBD) is a rising concern regarding their potential cancer risk. MEDLINE, EMBASE, and the Cochrane Library database were searched for articles regarding immunomodulators anti-TNF agents in IBD, hematologic malignancies, and solid tumors. Current evidences support that thiopurines and anti-TNFs used alone or in combination do not increase the overall cancer risk in IBD. Thiopurines use, with or without anti-TNFs, is associated with an increased risk of lymphoma, particularly non-Hodgkin lymphoma, in Crohn’s disease. Combined treatment significantly increases the risk of a rare hepatosplenic T-cell lymphoma, particularly in young male patients with Crohn’s disease. An increased risk of nonmelanotic skin cancer is also observed when using thiopurines in IBD, whereas a slightly increased risk of melanoma is observed when using anti-TNFs. The role played by immunomodulators in the development of other cancer types (i.e., urinary) as also by the severity of IBD is under investigation. Although the incidence of specific malignancies (lymphoma, skin cancers) seems to be increased by immunomodulators, their absolute number is low. As thiopurines and anti-TNFs are highly effective in IBD, current evidences support that in appropriate hands, their benefits overwhelm the cancer risk. However, a careful selection of both patients and timing of treatment is mandatory, particularly in young male patients with Crohn’s disease. Immunomodulators should therefore be handled by experienced and dedicated gastroenterologists who aware of the potential, although low, cancer risk associated with their use in patients with IBD. (Inflamm Bowel Dis 2015;21:674–698) Key Words: immunomodulators, inflammatory bowel disease, solid tumors, hematologic malignancies

I

n this review, current knowledge regarding the association between immunomodulators, including biologic therapies, and cancer in adult patients with inflammatory bowel disease (IBD) is reported. Data refer only to clinical evidences, whereas no studies regarding “in vivo” or “ex vivo” findings are included. MEDLINE, EMBASE, and the Cochrane Library database were all searched for articles and also for few abstracts referring to meetings published from 1967 to March 2014. In addition, the search also included recent abstracts from Digestive Disease Week. The review included only English language articles. The search was made including the terms “Inflammatory Bowel Disease and cancer,” “Crohn’s Disease and cancer,” “Ulcerative Colitis and cancer,” “azathioprine and IBD and cancer,” “6mercaptopurine and IBD and cancer,” “methotrexate and IBD and cancer,” “cyclosporine and IBD and cancer,” “anti-TNFs and IBD and cancer,” “biologic therapies and IBD and cancer”, “TNFs antagonists and IBD and cancer”, “certolizumab pegol and

Received for publication June 3, 2014; Accepted September 4, 2014. From the GI Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. The authors declare no specific conflict of interest related to the review. Not related to the review, L.B. received speaker fees from Zambon, MSD, and Abbvie. E.C. received speaker fees from Abbvie and MSD. F.P. received grant fees from Zambon and Takeda. Reprints: Livia Biancone, MD, PhD, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, 1, 00131, Rome, Italy (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000243 Published online 24 December 2014.

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IBD and cancer”, “adalimumab and IBD and cancer,” “infliximab and IBD and cancer,” “natalizumab and IBD and cancer,” “etanercept and IBD and cancer,” “immunomodulator and IBD and cancer,” and “immunosuppressive and IBD and cancer.” The search was also performed using, rather than the term “cancer,” the following terms: “malignancy,” “neoplasia,” “lymphoma,” “lymphoproliferative,” “leukemia,” “hematologic malignancies,” and “HSTCL.” In the text, the first 2 subheadings summarize the main findings regarding the risk of solid tumors and hematologic malignancies in patients with IBD not treated with immunosuppressives or biologics. Findings from these studies are briefly reported in the text but they are not summarized in the tables. Differently, findings regarding cancer and immunomodulators in IBD are reported in 4 tables: (1) Solid tumors in patients with IBD treated with immunomodulators and no anti-tumor necrosis factors (TNFs) (Table 1); (2) Hematologic malignancies in patients with IBD treated with immunomodulators and no antiTNFs (Table 2); (3) Solid tumors in patients with IBD treated with anti-TNFs with or without immunomodulators (Table 3); and (4) Hematologic malignancies in patients with IBD treated with anti-TNFs with/without immunomodulators (Table 4). Studies summarized in Tables 1–4 are sequentially reported according to the year of publication, both in the text and in each table. A low proportion of studies investigating the possible relation between immunomodulators and cancer in IBD are reported only in the text but not in the tables due to the limited number of tested patients or to the lack of available data. Tables 1–4 summarize the main characteristics of all the other studies mentioned in the text, including publication year, first author, Inflamm Bowel Dis Volume 21, Number 3, March 2015

Publication year Author

1994 Connell

1999 Korelitz

2000 Farrell

2002 Fraser

2007 Masunaga

2008 Kane

2009 Singh

Study type IBD total/ IMM-treated UC total (IMM, n) CD total (MM, n) Study period, yr Study population

Single-center 755 755 UC 282 CD 450 (IC 23) 1962–1991 United Kingdom

Single-center 591 550 170 380 1969–1997 NA

Single-center 782 238 109 129 1990–1999 Ireland

Meta-analysis 4039 4039 UC CD 1966–2006 NA

Single-center 40 23 NA NA 2005–2006 United States

Population-based 19,692 39 IMM only NA NA 2002–2006 Manitoba

Follow-up Patient-years IMM type

9 yr (2 wk–29 yr) 6975 AZA

NA

6.9 yr 1642 AZA, MTX, CyA

Single-center 2204 626 355 271 NA United Kingdom 6.9 6 5.5 yr 4319 yr AZA

1.7 yr

1 yr

AZA, 6 MP, CyA, Tacr 18–17.4 yr

NA

5 yr NA AZA, 6-MP, MTX

NA

NA

IMM duration, mean/median (range)

12.5 mo (2 d–15 yr)

6-MP 5 yr (5 mo–22 yr)

31 24.3 1.27 (P ¼ 0.18)

25 (16 CD, 9 UC) NA; 2.7/1000 NA

CRC Expected (n), (pt-yrs)

13 2.24

8 (1.6%) 5 CD, 3 UC

SIR (95% CI) or P NMSC BCC (n/expected) SCC (n/expected) SIR (95% CI)/incidence

1.27 (P ¼ 0.00001) 0 1 others 1 others 0

NA NR

Melanoma (n/expected)

0

NR

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SIR (95% CI) or P

NR

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P ¼ 0.0001

27 mo (1–222 mo)

NA 31/30 (4.5%) 4.5%; P ¼ 0.2 11a (2.2%) 8 UC; 7 CD; P ¼ 0.8

WMD 0.3 21.2 to 0.7; P ¼ NS NA

1 skin

NA

NA

NA

NA

NA

NA

NA

NA

NA P ¼ NS

NA

WMD 00 (20.9 to 1.9); P ¼ NS

Cancer and Immunomodulators in IBD

Any cancer (n) Expected (n), (pt-yrs) SIR (95% CI) or P

AZA 1.82 yr (1 mo-9 yr) MTX 1.8 yr; CyA 5 mo 30/238 7.06; 4.8/1000 4.25 (0.6–14.7); P ¼ 0.06 6/238 0.1; 28.3 (1.7–5); P ¼ 0.0001 9/544; P ¼ 0.4 2/238 1 (0.41); P ¼ 0.11 0 (0.14); P ¼ 0.32 5/544; P ¼ 0.9 1 (0.05)

Inflamm Bowel Dis Volume 21, Number 3, March 2015

TABLE 1. Solid Tumors in IBD Patients Treated with Immunomodulators and No Anti-TNFs


Others specified

SIR (95% CI) or P

Other not specified, n/expected/ incidence SIR or P Publication year Author Study type IBD total IMM-treated

Lung 3 (4.01); P ¼ 0.648

NR

Breast 2 (2.92); P ¼ 0.776 Anal canal 2 (0.03) P ¼ 0.0004 Stomach 2 (0.98) 2.04; P ¼ 0.257 Cervix 2 (0.5) P ¼ 0.09 7; 13.2; P ¼ 0.097

Breast 3

NA

Cervix: 12/23 (52%); 8/120 (6.6%); OR 4.5 (1.5–2.3); P , 0.001; 5/17 (29.4%); OR 1.9 (1.1–12)

Cervix: IMM alone: OR 1.01 (0.7–1.46); CD ¼ 0.82; UC 0.28; IMM + steroids: OR 1.41 (1.09–1.81); CD 0.56; UC 0.71

NA

NA

NA

Breast 5 (P ¼ 0.5) Urinary 4 (renal)

0.5%; (2 CD, 1 UC)

NR

Lung: 1; P ¼ 0.9

1; 1.43; P ¼ 0.32

6; +3 lymphoma

2010 Armstrong

2011 Peyrin-Biroulet

2011 Singh

2011 Van Shaik

2013 Jess

2013 Pasternak

Population-based

Population-based

Population-based

Single-center

Population-based

15,441 1955

19,486 (8676) Using: 5867; Discontinued: 2809; No: 10810 UC: N ¼ 7727 (2070) Using: 1415; Discontinued: 655; No: 5657 CD: N ¼ 11,759/6606 Using: 0.4452; Discontinued: 2154; No: 5153 2004–2007 France 35 mo (29–40)

9618 1749

2887 819

2211 602

Populationbased 45,986 5197

4743 (553) 4875 (1196)

NA

143 (/257) 774 (345)

23,913 22,073

NA NA

Before 2008–2009 Manitoba 117,388 pt-yrs

NA Germany 18,663 pt-yrs

1978–2010 Denmark UC 3962 pt-yrs

1997–2008 Denmark 7.9 pt-yrs

1987–2012 Multinational Mean years: (1.32– 12.17)

49,719 pt-yrs

1.115,361 pt-yrs

CD 5190 pt-yrs

IQR 3.5–12.0

NA

CD total (IMM, n)

NA

1987–2001 United Kingdom NA

Patient-years

2015

2014 Ariyaratnam Metaanalysis 60,351


UC total (IMM, n)

Study period, yr Study population Follow-up

NA

Biancone et al

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TABLE 1 (Continued)

IMM type IMM duration, mean/ median/range Any cancer (n)

AZA

AZA, 6-MP

AZA, 6-MP, MTX

AZA, 6-MP

AZA, 6-MP

AZA

NA

NR

NA

.6 mo

NA

OR 1.08 (0.78–1.51)

NA

NA

NA

92; UC 34 (exp 30.5)

Duration 1.9 yr Overall: RR, 1.41 (1.15– 1.74) Urinary tract: RR, 2.84 (1.24– 6.51)

Expected (n) (pt-yrs)

SIR 1.11 (0.77–1.56)

SIR (95% CI or P) CRC Expected (n) (pt-yrs) SIR (95% CI) or P NMSC

NA

OR 0.99 (0.35–2.81)

BCC (n/expected); SCC (n/expected); SIR (95%CI); P

Melanoma (n/expect); SIR (95% CI) or P Others; SIR (95% CI) or P

NA

NA

32 (11.1%)

237

86 (3%); 4.4/1000

NMSC: Using HR, 5.9; NMSC: HR, 1.35 (0.90–2); BCC 2.1–16.6; HR, 1.16 (0.74–1.82); SCC P ¼ 0.0006; HR, 5.21 (3.04–13.3) Discontinued: HR, 3.9; 1.3–12.1; P ¼ 0.02 NA NA

NR Lung 0.96 (0.29–3.13); GI 0.68 (0.35–1.29); Breast 0.47 (0.11–1.97) NR

NR

NA

NR

HR, 2.28 (1.50– 3.45)

HR, 0.85 (0.51–1.41); (4.7/1000 in C)

NA

NA

NR

NA

NA

NR

NR

Genital cancers: UC; SIR 0.82 (0.1–2.96); Cervical dyplasia: CD; SIR 2.47 (1.54–3.73)

Lymphoma

NA

NR

NR

NR

NR

NR

NR


a DALM or dysplasia in 4 IBD and in 9 C No IMM. C, controls; NR, not reported; NA, not applicable; SIR, standardized incidence ratio; WMD, weighted mean difference.

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NA


Other not specified (n/expected/ incidence SIR); P

NA

CD 58 (exp 31.39) SIR 1.85 (1.40–2.39) UC SIR 0.82 (0.1–2.95) CD SIR 1.41 (0.29–4.1) SBC, 46.09 (5.58–166.4) NA

AZA or 6MP NA


TABLE 1 (Continued)


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TABLE 2. Hematologic Malignancies in IBD Patients Treated with Immunomodulators and No Anti-TNFs Publication year Author

1994 Connell

1999 Korelitz

2000 Farrell

2001 Lewis

2002 Fraser

Single-center

Singlecenter 591 (550)

Single-center

Population-based

Single-center

782 (238)

1465

2204 (626)

UC 302 CD 453 1962–1991 United Kingdom 9 yr (2 wk–29 yr) 6975 AZA

170 380 NR United States 5.9 yr

109 129 1990–1999 Ireland

10,391 (628) 6605 (837) 1988–1997. United Kingdom

IMM duration, mean/median/ range Any cancer (n)

12.5 mo (2 d–15 yr)

Expected (n) Incidence (pt-yrs) SIR (95% CI or P)

5 yr (5 mo–22 yr) 25 (16 CD/9 UC) NA 2.7/1000 NA

24.3 NR 1.27 (P ¼ 0.18) 1 (NHL) 2 NHL (2 CD) 0.52 NR P ¼ 0.69 0.22/1000 pt-yr SIR 0 SIR 4.9 (0.9– 14.5)

Study type IBD total (IMM-treated) UC total (IMM, n) CD total (IMM, n) Study period, yr Study population Follow-up (range) Patient-years IMM type

Lymphoma (n) Expected (n) Incidence SIR (95% CI) or P

755 (755)

31

6-MP

1 NR NR

Publication year Author Study type IBD total IMM-treated

678

1 0.11/1000

6.9 yr 1642 AZA, 6-MP, MTX, CyA AZA 1.82 yr (1 mo–9 yr); MTX 1.8 yrs; CyA 5 mo 30/238

UC 2.72 6 2 yr AZA, 6-MP CD 2.14 6 2.1; UC 1.90 6 1.9; C 2.37 6 2.7

AZA 27 mo (1–222 mo) 31/30 (4.5%)

7.06 4.8/1000 4.25 (0.6–14.7); P ¼ 0.06 4 NHL (2AZA)

IBD 1.27

3 (2 NHL)

0.13 0.64/1000

95% CI, 0.03–8.20 UC 3.27

0.47% P ¼ 0.5

31.2 (2.0–85) P ¼ 0.0001

95% CI, 0.08–18.2

2015

Metaanalysis 3891

Meta-analysis 4039 (4039) UC CD 1966–2006 NA 1.7 yr

AZA, 6-MP AZA, 6 MP, CyA, Tacr 18 mo–17.4 yr

NR

WMD 0.3 (21.2 to 0.7); P ¼ NS)

NR

0

11 (9 NHL, 2 WMD 0 (20.8 to 0.7) HL) 2.63 100.000 ptLeukemia n ¼ WMD yrs 20.1 (20.4 to 0.3) Age 20–29 yr: 7.65 Age 70–79 yr: 93.90 SIR 4.18 (2.07– 7.51) 0

0

0

2009 Beaugerie

2010 Armstrong

2012 Sokol

2013 Jess

2013 Pasternak

2014 Kotlyar

Population-based


Cohort study

Population-based

Meta-analysis

19,486 (5867) Using 16,659; Disc. 9981; No 23,073

2211 602


19,486/5867 Using 5867; Disc. 2809; No 10,810


0

2007 Masunaga

355 UC 271 CD NA 1996–2000 United Multinational Kingdom CD 2.99 6 2.1 yr 6.9 6 5.5 yr 2.87–9 yr

SIR 59

Leukemia (n) Expected (n) SIR (95% CI) or P

2005 Kandiel

34,190 34.190



TABLE 2 (Continued) UC total (IMM, n) CD total (IMM, n) Study period, yr Study population

7727

NA

7727 (2070)

143 (/257)

23,913

20,490

1179

NA

11,759 (6606)

774 (345)

22,073

13,379

2004–2007 France

1987–2001 United Kingdom NA

2004–2007 France

1978–2010 Denmark

1997–2008 Denmark

1985–2013 Multinational

Follow-up/range

35 mo (IQR 29–40)

35 mo (29–40)

UC 3962 pt-yrs

7.9 pt/yrs

2.97–9.94 yr (range of the means)

49,713 pt-yrs

CD 5190 pt-yrs

AZA, 6-MP 49,713 pt-yrs; Pt-yrs: ongoing: 16,659; Discontinued: 9981; Never 23,071 NA

AZA, 6-MP NA

IQR 3.5– 12.0 AZA 1.9 yr

Patient-years IMM type IMM duration, mean/median (range) Any cancer (n); expected (n); incidence (ptyrs); SIR (95% CI, P) Lymphoma (n)

AZA, 6-MP (current/past) Total 35 (29.2–39.5); using: 35.7 (31.1–40.1); discontinued: 35.4 (29.9–4); never 34.3 (27.7–39) NR

HR, 5.28 (95% CI 2.01–13.9)

Leukemia (n); Expected (n); SIR (95% CI) or P

OR 1.08 (0.78–1.51)

OR 3.22 (1.01– 10.18)

n ¼ 17; 15 using; 2 discontinued

Expected (n)

SIR (95% CI), P

AZA NA

NHL, HL: incidence: pt-yrs (95% CI): ongoing 0.90/1000 (0.50–149); discontinued 0.2/ 1000 (0.02–0.72); Never 0.26/1000 (0.10–0.57); P ¼ 0.005 versus discontinued/never NR

6

Ongoing: 4 (expected 0.08) 49 (13.4–126.8; P , 0.0001); discontinued 1 (expected 0.05) 18.22 (0.4–101.5); P ¼ 0.13; never: 1 (expected 0.21) 4.83 (0.12–26.91; P ¼ 0.37)

92; UC 34 (exp 30.5); SIR 1.11 (0.77–1.56); CD 58 (exp 31.39); SIR 1.85 (1.40– 2.39) SIR 2.85 (0.35– 10.30) versus no thiopurines SIR 3.73 (1.21–8.7)

RR 1.41 (1.15– 1.74)

NA

RR 2.40 (1.13– 5.11) n ¼ 12

91; expected 20.2

Expected 3.52; SIR 1.64 (0.98– 2.75)

NR

NR

NR

AZA, 6-MP NA

NR

SIR 4.49 (2.81– 7.17)

Using: 5.71 (3.22–10.1); Past: 1.42 (0.86–2.34); Never: 1.06 (0.81–1.40) NR

C, controls; SIR, standardized incidence ratio; WMD, weighted mean difference.

study type, total number of IBD (ulcerative colitis [UC] and Crohn’s disease [CD]) patients, and number of patients treated with immunomodulators and/or anti-TNFs study period and population, follow-up (mean/median or pt-yrs), immunomodulators and/or anti-TNFs type and duration. Characteristics of cancer

summarized in each table include observed number, expected, incidence (pt-yrs), SIR (95% confidence interval [CI]) in IBD. All these variables were always reported for hematologic cancers (Tables 2 and 4). Differently, for solid tumors (Tables 1 and 3), the above reported details are always reported for overall www.ibdjournal.org |

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TABLE 3. Solid Tumors in IBD Patients Treated with Anti-TNFs with or Without Immunomodulators Publication year Author

2006 Biancone

2006 Bhatia

2008 Caspersen

2008 Peyrin-Biroulet

2009 Fidder

Multicenter

Single-center

Single-center

Single-center

IBD total (antiTNFs/IMM) UC total/anti-TNFs (n) CD total/anti-TNFs (n) Study period (yr or pt-yrs) IBD Study population Follow-up pt-yrs

808 (404, 233)

116 (76)

651 (651)

Meta-analysis trials 5356 (3341)

1400 (734, 669)

0

52 (21)

15

0

270 (137)

808 (404)

64 (55)

619 (17 CUNC)

5356 (3341)

1126 (597) (CUNC 14/9)

1999–2004

NA

1999–2005

1994–2008

Italy 48 (6–396)

United States NA

Denmark 29.1 mo (0.1–72)

1997–2007 (trials publication) Multinational 24 wk (4–60)

Anti-TNFs type (n)

IFX

IFX 12 (+AZA 9; 6-MP 55)

IFX

Anti-TNFs duration Mean/median (range) Combined IMM (Y/N) Mean/median (range) Any cancer (n) Expected (n) Incidence (pt-yrs)

3 (range 1–30) Infusions, median

NR

3351 infusions 3 infusion./pt (1–42)

Y (203)

Y

Y

SIR (95% CI or P)

NR (CD-C 7/404)

CRC (n/expected) Incidence/SIR (95% CI) or P NMSC (n/expected) IBD BSC (n/expected) IBD SCC (n/expected) SIR (95% CI)/ incidence IBD Melanoma (n/expected) SIR (95% CI) or p Others specified (n/expected); SIR (95% CI)

0/404 NR

NR

1 (NR) NR

1/404 (CD-C: 2/404)

NR

0

Study type

680

36 (3–160) 9/404 NR NR

IFX, ADA, CTZ, CDP571, Ocpt, Etcp 4–52 wk trials

NR

447 IBD (AZA, MTX) NR

4 (4 CD) 5.9 NR SIR 0.7 (0.2–0.7)

Denmark 58 mo (IQR, 83–88); 3775 (IBD-C, 6704) IFX, ADA, CTZ, DCZM

7276 infusions; 6 (3–12)

AZA, 6 MP 501; MTX 168 AZA, 6 MP 385; MTX 39; CyA 41

8 NR 0.24% (95% CI, 20.45 to 0.18) P ¼ 0.56 (C: 8; 0.39%) NR

NR

23 cancer in 21 patients (1.64%) NR NR (C: 41 cancer/39 patients 5.8%) 0/NR NR (C: 8/NR + 1 ethmoid cancer) 8 (NR)

1 (CD-C: 1/404)

0

6 (NR)

0 (CD-C: 1/404) NR

0 NA

2 (NR) NR 5 (BCC 4; SCC1)

0 0 Anal canal 2; GI overall 3; Lung 0; Breast 3; Larynx 1


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NR

Cervix 14/68; 0.38%; P ¼ NS 7/49 (21%); P ¼ 0.38; IBD no ISS 6/116 (5.2%); P ¼ NS

1 (NR) NR GI overall 2 (1 rectum, 1 esophagus); genitourinary 1 ovary

NR

NR

2 (NR) 2 (NR) Pancreas 1, Breast 1, Cholangiocarcicoma 1, Genitourinary 4 (Cervix 2, Renal 1, Endometrial 1)



TABLE 3 (Continued) Publication year Author

2010 Long-cohort study

2010 Long-nested-case control

2012 Long-nested case-control

2012 Lichtenstein

Study type IBD total (anti-TNFs/ IMM)

Population-based 53,377 (136, 723)

Population-based Cases (NMSC): 742 (38, 182); controls (no NMSC): 2968 (63, 274) 355 387 1996–2005 United States 483 d (IQR 266–777); NR

Single-center 1032 (82, 184)

Meta-analysis trials 2385 (1920, 0)

Melanoma, 520 (16, 65) 504 (66, 118) 1997–2009 United States 24 mo (IQR 12–43)

741 (493, 0) 1644 (1427, 0) NR Multinational NR

IFX, ADA NR

IFX, ADA, CTZ NR

AZA/6 MP, MTX, CyA; Micofenolato Mofetil; Tacrolimus NR

AZA, 6-MP

UC total (anti-TNFs, n) 26,974 CD total (anti-TNFs, n) 26,403 Study period (yr or pt-yrs) 1996–2005 Study population United States Follow-up; pt-yrs UC: 700 d (456–988); CD: 730 (IQR 456– 1004) Anti-TNFs type (n) IFX, ADA Anti-TNFs duration/n/ NR median Combined IMM (Y/N); mean/median (range) Any cancer (n)

AZA, 6 MP, MTX, CyA; Micof. Mofetil; Tacrol NR

Expected (n)

NR

Incidence (pt-yrs)

NR

SIR (95% CI or P)

NR

CRC (n/expected) NMSC (n/expected) IBD BCC (n/expected) IBD

SCC (n/expected)

SIR (95% CI/Incidence)

NR NR IBD: 733 NMSC/ NMSC: IBD: 733/100,000 100,000 IBD IRR, 1.64 (1.51– AZA/6 MP: Recent OR 3.56 (2.8– 1.78) 14.5); Persistent OR 4.27 (3.08–5.92) CD IRR, 1.84 (1.63– Anti-TNFs: recent OR, 2.07 2.06) (1.28–3.33); persistent OR: 2.18 (1.07–4.46) UC IRR, 1.47 (1.31– 1.65)

Melanoma (n/expected); SIR (95% CI) (Controls (n/exp)

NR

NR

Others specified; SIR (95% CI)

NR

NR

NR

NR IBD 3288 (C-no NMSC 12,945)

IFX CD: IFX 6.1–7.5 infusions; UC: IFX 6.3–4.5 infusions AZA, 6-MP, MTX

IBD: IFX 11 (0.6%; Placebo; 2 (0.4%); P¼1 UC IFX 5 (1%); Placebo 0 (0.0%); P ¼ 0.1 CD-IFX 6 (0.4%); Placebo 2 (0.9%) P ¼ 0.2 CD IMM 1.84 (0.22– 6.66) versus CD noIMM 0 (0–9); SIR ¼ 5.7 NA NA

NMSC-Anti-TNFs; IBD 1.14 (0.95–1.36) CD: 1.16 (0.95–1.41); UC: 1.06 (0.69–1.64) NMSC-IMM: IBD 1.85 (1.66– 2.05) CD 1.99 (1.73–2.27); UC 1.63 (1.36–1.94) IBD: 209 (C-no melanoma 823) Anti-TNFs; IBD: 1.88 (1.08– 3.29): CD 1.94 (1.03–3.68); UC: 1.73 (0.53–5.63); IMM: IBD: 1.10 (0.72–1.67); CD: 0.92 (0.53–1.59); UC: 1.31 (0.66–2.60) NR

NA

NA


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TABLE 3 (Continued) Publication year Author Study type

2014 Williams APT

2014 Lichtenstein

2014 Osternan

2014 Singh

2014 Williams APT

Meta-analysis trials

Cohort

Meta-analysis

Meta-analysis trials

7054 (4135)

CD: 6273 (3764, NR)

Pooled analysis ADA trials 1594

172,837

7054 (4135, 7052)

2488

0

0

79,360

2488

4566

6273 (3764)

CD

4566

1946–2013 Multinational

July 2009–February 2010 North America

NA Multinational

NR IFX, ADA, CTZ, golimumab $14 d NR

5.2 yr ($5 yr); IFX 17.712 pt-yrs IFX

3050 pt-yrs ADA

92.208 (+1269 CUNC) 1966–2012 United States, Europe NR IFX, ADA

76 yr 20,931 pt-yrs

Y NR

2686/6273 CD IFX-treated: 1780/3764

16/4135 (0.39%)

139/3764 (3.69%)/0.78/100 ptyrs; OR 0.90 (0.69–1.1.8); P ¼ 0.46 HR, 0.59 (0.28–1.22); P ¼ 0.16

ADA 1.25 (0.04–5.54) ADA + IMM 1.61 (0.04–5.52) Y 694/3050 patients (44%) ADA 44 in 34 (2.1%)

IBD total (anti-TNFs, IMM) UC total (anti-TNFs, IMM) CD total (anti-TNFs, IMM) Study period IBD Study population Follow-up, pt-yrs Anti-TNFs type (n) Anti-TNFs duration IMM duration Combined IMM (Y/N) Mean/median (range) Any cancer (n)

Expected (n)

NR

Incidence (pt-yrs)

NR

SIR (95% CI or P)

0.77 (95% CI, 0.37–1.59) 3

CRC (n/expected) Incidence/SIR (95% CI), P NMSC (n/expected) IBD BCC (n/expected) IBD SCC (n/expected) SIR (95% CI)/ incidence IBD

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IMM HR, 1.43 (0.92–2.21); P ¼ 0.11 Combo: HR, 1.22 (0.81–1.86); P ¼ 0.34 13/7.29; rate, 0.07 pt-yrs

3

1.78 (0.95–3.05); IMM 10/8.97; SIR 0.53–2.05 0.16 pt-yrs (29)

2

0.09 pt-yrs (16)

1

0.05 pt-yrs (9)

NR

RR 0.89 (0.45–1.74)

NR

1946–2013 Multinational NR IFX, ADA, CTZ, golimumab $14 d NR

NR

Y NR

NR

16/4135 (0.39%)

Versus general population, no NMSC: ADA: SIR, 0.63 (0.17–1.62); Combo: SIR 3.04 (1.6–5.1); ADA versus combo 2.82 (1.07–7.4)

NR

NR 0.77 (0.37–1.59) NR

NR

3 NR

Versus general population ADA mono: 1.2 (0.39–2.8) ADA + IMM: 3.26 (1.04–10.25) Combo versus ADA mono: NMSC: SIR 3.46 (1.08–11.06)

NR

3 2 1 NR



TABLE 3 (Continued) Melanoma (n/expected)

0

7 pt-yrs (0.04)

NR

0

Others specified SIR (95% CI)

Lung 2; Breast 1; CRC 3, Gastric 1; Thyroid 1; Genitourinary 3; unknown 1; AdenoK 1

Solid tumors 0.42 pt-yrs (75); RR, 0.92 (0.66–1.28); Lung 9 (0.05); Breast 10 (0.06); Cervix 1 (0.01); Genitourinary 10: prostate 4 (0.03); renal 5 (0.04); bladder 1 (0.01); thyroid 2 (0.02); bone 1 (0.01); liver 0.02 (3); esophagus 0.01 (1); peritoneal 0.01 (2); oral, pancreas, SBC: 0.02 (3)

NR

Anti-TNFs versus no anti-TNFs: 1.08 (0.59– 1.96) AZA/6 MP versus no AZA/6 MP: RR, 1.10 (0.73–1.66) NR

0

Lung 2; breast 1; thyroid 1; genitourinary 3 (bladder 1; kidney 1; prostate 1) met.. adenoK 1, unknown 1; stomach 1

C, controls; CUNC, colitis unclassified; SIR, standardized incidence ratio.

cancers, whereas additional specific cancer histotypes are detailed in relation to those reported in each study. Because of the different study design across the studies, heterogeneity was observed in terms of available data. Studies investigating the role of immunomodulators in determining the risk of 1 single cancer type (i.e., cervix) are also summarized in the tables.

REVIEW OF THE LITERATURE Solid Tumors in Patients with IBD Not Treated with Immunomodulators CD and UC are characterized by a chronic inflammation of the bowel with possible involvement of extraintestinal sites.1 Growing evidences indicate that chronic inflammation of the intestinal mucosa is a main trigger for the development of colorectal cancer (CRC) in IBDs.2 An increased risk of CRC has indeed been reported in patients with UC and CD colitis, independent of immunomodulators and anti-TNFs use.1–3 The risk of CRC is higher in longstanding IBD colitis and in patients with associated primary sclerosing cholangitis (PSC).1–3 Several experimental models of colitis support a clear relationship between chronic inflammation and CRC.4 Accordingly, the risk of small bowel carcinoma (SBC) also has been reported to be higher in patients with small bowel CD, independent of the use of immunomodulators.5 In 2011, a population-based study reported a risk of CCR and SBC versus the general population of 1.4 to 1.9 and 21.1 to 27.1, respectively.6 More recently, in 2012, a population-based cohort study supported that age was the only characteristic

associated with IBD-associated CRC and that the prognosis may be poorer in IBD.7 Among the 19,451 cases of CRC recorded between 1976 and 2008, 38 cases of IBD-associated CRC were identified (29 UC, 9 CD). The mean age at diagnosis of CRC was lower in IBD (56.9 yr) than in non-patients with IBD (70.9 yr; P , 0.001). Only age was independently associated with IBD-associated CRC (odds ratio [OR], 0.22; 95% CI, 0.12– 0.43; P , 0.001). Relative survival at 5 years was comparable between patients with CRC with or without IBD (relative survival, 51.9%; 95% CI, 51.1–52.8 versus relative survival, 41.3%; 95% CI, 24.6–57.2; P ¼ 0.201).7 In 2012, a meta-analysis of population-based cohort studies reported an average of 1.6% of patients with UC with a diagnosis of CRC during 14 years of follow-up.8 A 2.4-fold increased risk of CRC was observed in UC (95% CI, 2.1–2.7), particularly in males, at young age and with extensive UC (standardized incidence ratio [SIR] [95% CI], 2.6 [2.2–3.0]; women, 1.9 [1.5–2.3]; 8.6 [3.8– 19.5]; 4.8 [3.9–5.9], respectively). More recently, discrepant findings are reported regarding the increased risk of CRC in UC and CD colitis.9,10 A role for a long-term treatment with mesalazine has been proposed for the suggested lower frequency of CRC in IBD during the last years.11 In 2013, a prospective observational cohort of patients with IBD assessed the risk of colorectal high-grade dysplasia and cancer.12 Data from 19,486 patients with IBD (60.3% CD, 30.1% receiving thiopurines) were followed from May 2004 until December 2007. Findings supported that patients with IBD with longstanding extensive colitis show an increased risk for CRC, and that this risk is lower among patients treated with thiopurines. Among the 19,486 patients with IBD, 37 developed CRC and 20 www.ibdjournal.org |

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TABLE 4. Hematologic Malignancies in IBD Patients Treated with Anti-TNFs with or Without Immunomodulators Publication year Author

2006 Biancone

Study type Multicenter pair IBD total (anti-TNFs, IMM, n) 808 (404, 233) UC total (anti-TNFs, IMM, n) 0 CD total (anti-TNFs, IMM, n) 808 (404, 233) Study period, yr 1999–2004 Study population Italy Folllow-up (median/mean/range) 48 (6–396) Patient-years Anti-TNFs type IFX Combined IMM (Y/N), Infusion number, 3 mean/median (range) (1–30) Anti-TNFs duration, Y (203), 36 mean/median (range) (3–160) Any cancer (n)

2009 Fidder

2011 Herrinton

Meta-analysis Trials 8905 0

Single-center 1400 (734) 270 (137) 1126/597 (CUNC 14/9) 1994–2008

Population-based 10,423, 1442, 3945 UC, CD

1950–2007 Multinational 74 wk 21,178 pt-yrs IFX, ADA, CTZ Y, 5877 (66%) NR

0/404

13 (NHL)

NR

6.1/10,000 pt-yrs

NR (CD no anti-TNFs: 3 NHL)

1; NR

Expected: 1.9/10,000 pt-yrs; 3.23 (95% CI, 1.5–6.9) versus SEER 1.7 (95% CI, 0.5–7.1) versus CD + IMM; men, age 20–54: 5.4 (95% CI, 1.3–18.1) 0

1 (chronic myeloid)

NR

NR NR NR (C: 7/404)

Lymphoma (n) Incidence Expected (n) SIR (95% CI) or P

Leukemia (n), expected (n); SIR (95% CI) or P Publication year Author Study type IBD total (anti-TNFs, IMM, n) UC total (anti-TNFs, IMM, n) CD total (anti-TNFs, IMM, n) Study period, yr Study population Follow-up (mean/median/range); pt-yrs


2015

58 mo (IQR 83–88) 3775 (IBD-C 6704) IFX, ADA, CTZ, daclizumab 7276 infusions; 6 (3–12) Y; AZA/6 MP 501; MTX 168; AZA/6 MP 385; MTX 39; CyA 41 23 cancer in 21 patients (1.64%) NR NR NR; 41 cancer in 39 patients (5.8%) 2 (1 HL/1 NHL)

9/404

Expected (n) Incidence (pt-yrs) SIR (95% CI or P)

684

2009 Siegel

1

1996–2009 United Kingdom Anti-TNFs or IMM 21,282 pt-yrs IFX, ADA Y (AZA/6 MP) TNF/IMM 21,282 pt-yrs

NR

43 IBD (0.26%; HD 12%; N ¼ 5) AZA-6MP: ongoing 1.4 (1.2–2.7); past 0.3 (0.2–0.4) Anti-TNFs: Ongoing, 4.4 (3.4–5.4); Past, 5.5 (4.5–6.6)

0

2012 Lichtenstein

2013 Lakatos

2013 Khan

Pooled analysis trials 2385 (1920, 0)

Population-based 1420 (63, 299)

Population-based 4734 (251, 5089)

741 (493, 0) 1644 (1427,0) NA Multinational UC-IFX 832/1.0; 0.6 (0.20–1.40) pt-yrs CD-IFX 1229/1.0; 0.49 (0.18– 1.06) pt-yrs IBD-IFX: 2061/1.0; 0.53 (0.27– 0.95) pt-yrs

914 (9, 68) 506 (54, 232) 1977–2010 Hungary 19,293 pt-yrs (median 13 pt-yrs)

4734 (251, 5089) 0 2001–2011 United States 5.72 yr (IQR, 2.25–8.87)



TABLE 4 (Continued) Anti-TNFs type Combined IMM (Y/N); mean/ median (range) Anti-TNFs duration Mean/median (range) Any cancer (n) Expected (n) Incidence (pt-yrs); SIR (95% CI or P) Lymphoma (n); expected (n) SIR (95% CI) or P

Leukemia (n), expected (n), SIR (95% CI) or P

IFX AZA, 6-MP, MTX; 947 IBD Mean infusions CD, 6.1–7.5; UC, 6.3–6.5 IBD: IFX 11 (0.6%; placebo 2 (0.4%); P ¼ 1 UC: IFX 5 (1%); placebo 0 (0.0%); P ¼ 0.1 CD: IFX 6 (0.4%); placebo 2 (0.9%); P ¼ 0.2 IBD 2 (0.1%); 0.1/100 pt-yrs; P ¼ 1

n ¼ 11; only anti-TNFs 52 IBD; AZA 2549 IBD pt-yrs NR NR

0 in AZA/TNFs-treated versus 0.41 expected; P ¼ NS

CD: 2 (0.1%); 0.16/100 pt-yrs; P ¼ 1

IBD: 3 (1 HL, 2 NHL)

UC: 0 (0%); 0/100 pt-yrs; P¼0

Incidence 55/10,000 pt-yrs

0

0

IFX Y (AZA, 6 MP); 0.97 yr (IQR, 0.28–2.5) NR 177 combined IFX + AZA, 6-MP NR

23 NH (18 ongoing; 5 discontinued AZA, 6-MP) SIR 3.75 (2.5–5.62) During: IMM 2.31/1000 pt-yrs; Discontinued: 0.28/1000 pt-yrs; Never: 0.60/ 1000 pt-yrs During: HR, 4.2 (2.5–6.8); P , 0.0001; discontinued: HR, 0.5 (0.2–1.3); P ¼ 0.17 0

Publication year Author

2014 Williams APT

2014 Lichtenstein

2014 Osternan

2014 Lopez

Study type

Meta-analysis trials 7054 (4135, 7052) 2488

Cohort

Pooled analysis trials

Population-based

CD: 6273 (3764, NR)

1594

19,486 (1938, 8676)

0

0

NR

4566

6273 (3764)

CD

NR

1946–2013 Multinational NR

July 2009–February 2010 North America mean 5.2 yr ($5 yr); IFX 17.712 pt-yrs IFX

NA Multinational 3050 pt-yrs

1980–2009 French 36 mo; 49,736 pt-yrs

ADA

IFX

NR

ADA 1.25 (0.04–5.54)

Y (AZA, 6-MP, MTX, others)

NR

NR

ADA + any IMM: 1.61 (0.04–5.52)

NR

Y

2686/6273 CD

Y

NR

NR

IFX-treated: 1780/3764

694/3050 patients (44%)

16/4135 (0.39%)

139/3764 (3.69%)/0.78/100 pt-yrs

ADA: 44 in 34 patients (2.1%)

IBD total (antiTNFs, IMM) UC total (antiTNFs, IMM) CD total (antiTNFs, IMM) Study period, yr Study population Follow-up (range) patient-years Anti-TNFs type

Combined IMM (Y/N) Mean/median (range) Anti-TNFs duration Mean/median (range) Any cancer (n)

IFX, ADA, CTZ, golimumab $14 d

NR


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TABLE 4 (Continued) Expected (n)

NR

OR 0.90 (0.69–1.1.8); P ¼ 0.46;

Incidence (pt-yrs)

NR

SIR (95% CI or P)

0.77 (95% CI, 0.37–1.59

3 (0.1%)

HR, 0.59 (0.28–1.22; P ¼ 0.16) IMM: HR, 1.43 (0.92–2.21); P ¼ 0.11; Anti-TNFs + IMM: HR, 1.22 (0.81–1.86); P ¼ 0.34 0.05 (8)

Expected (n) SIR (95% CI), P

(2 NHL, 1 HL)

0.01 (1)

Leukemia (n), expected (n) SIR (95% CI), P

0

0.05 (7)/0.03 (4) 0

Lymphoma (n)

Versus general population: Any cancer no NMSC: ADA: SIR 0.63 (0.17–1.62); combo: SIR 3.04 (1.6–5.1); ADA versus combo: 2.82 (1.07–7.44)

Lymphoma versus general population: ADA mono: SIR, 1.2 (0.39–2.8); ADA + any IMM: 3.26 (1.04–10.25); ADA + IMM: SIR, 8.03 (0.97–29.0)

Lymphoma NR: Acute myeloid disorders: n ¼ 5; ongoing IMM: n ¼ 1 (expected 0.65) 6/100,000 pt-yrs; SIR, 1.54 (0.05–8.54); past IMM: n ¼ 3 (expected 0.43) 30/100,000 pt-yrs; SIR, 1.54 (0.05–8.54); 30/100,000 ptyrs; SIR, 6.98 (1.44–20.36); Never: n ¼ 1; 4/100,000 pt-yrs

0

0

C, controls; CUNC, colitis unclassified; SIR, standardized incidence ratio.

colorectal HGD (SIR of CRC: all patients with IBD, 2.2; 95% CI, 1.5–3.0; P , 0.0001; patients with versus without longstanding extensive colitis, 7.0 [95% CI, 4.4–10.5]; P , 0.001 versus 1.1 [0.6–1.8]; P ¼ 0.84). The adjusted hazard ratio (HR) for colorectal HGD and cancer was reduced in patients treated versus never treated with thiopurines (0.28; 95% CI, 0.1–0.9; P ¼ 0.03).12 The risk of SBC also has been reported to be increased in patients with small bowel CD, independent of treatments with immunomodulators.5 In 2013, Elriz et al13 evaluated, in a prospective observational CESAME study, the risk and incidence of SBC in a large prospective cohort of 11,759 patients with CD versus the general population. CD involved the small bowel in 8222 (69.9%) patients. SBC in the involved ileum occurred in 5 patients with small bowel CD (4 patients died of SBC at 7 yr). The incidence rates of SBC were 0.235/1000 pt-yr (95% CI, 0.076–0.547; SIR, 34.9 [95% CI, 11.3–81.5]) in patients with small bowel CD and 0.464/1000 pt-yr (95% CI, 0.127–1.190; SIR 46.0 [95% CI, 12.5–117.8]) in patients with small bowel CD for .8 years. Findings supported that SBC in small bowel CD has a poor prognosis, supporting the need of small bowel endoscopic screening in highrisk patients.13 During the last few years, an increased risk of non-

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melanotic skin cancer (NMSC) and melanoma has also been reported in IBD, independent of immunomodulatory treatments.14 An increased frequency of lung cancer has been reported in CD, although this observation has been associated with a higher frequency of smokers among patients with CD, when compared with the general non-IBD population.15 In CD, a higher frequency of cancer of the anal canal has also been reported, particularly along fistulous tracts.16 In a monocentric study, fistulizing CD and pancolitis in UC have been associated with a higher risk of any cancer.17 An independent study in the Danish population also supported that clinical characteristics of IBD at excess risk differ by cancer subtype.18 Although larger multicenter studies are required, present preliminary observations suggest that patients with IBD with a more severe disease (i.e., fistulizing CD and pancolitis in UC) conceive a higher cancer risk related to an ongoing severe chronic inflammation. It is therefore conceivable that this subgroup of patients with IBD may bear a higher cancer risk related to both a persistent severe inflammation and to a subsequent more frequent use of immunomodulators and biologics, involved in the development of specific cancer histotypes (i.e., lymphoma, NMSC, melanoma).17,18


In 2014, Kappelman et al19 in a nationwide cohort study evaluated the incidence of cancer in patients with IBD compared with that expected in the general population.19 Cancer occurred in 772 of 13,756 patients with CD (SIR 1.3; 95% CI, 1.2–1.4) and in 2331 of 35,152 patients with UC (SIR, 1.1; 95% CI, 1.0–1.1). CD was weakly associated with gastrointestinal and extraintestinal cancers (SIR [95% CI], 1.2 [1.0–1.4] and 1.3 [1.2–1.4], respectively), showing the strongest associations for hematologic malignancies, smoking-related cancers, and melanoma (SIR [95% CI], 1.9 [1.5– 2.3], 1.5 [1.3–1.8], 1.4 [1.0–1.9], respectively). In UC, a weak association was observed with gastrointestinal and extraintestinal cancers (SIR [95% CI], 1.1 [1.0–1.2] and 1.1 [1.0–1.1], respectively).19 In 2014, Kim et al20 in a population-based cohort study, assessed the risk of high-grade cervical dysplasia in women with systemic inflammatory disease (including psoriasis, RA, SLE, IBD; n ¼ 133,333) compared with woman without systemic inflammatory disease (n ¼ 533,332).20 Over the mean follow-up of 2.1 years, the adjusted HR in IBD was 1.07 (95% CI, 0.79–1.45).20 Regarding this, a recent ECCO workshop reported that although the risk of uterine cervix abnormalities is increased in IBD women, irrespective of the use of immunosuppressants. On the basis of this observation, it is recommended that all women with IBD, particularly those receiving immunosuppressants, adhere to a screening program of cervical surveillance and undergo HPV vaccination, when appropriate.21 In 2014, Ananthakrishnan et al22 evaluated, in a multi-institutional IBD cohort, whether PSC is associated with an increased risk of extraintestinal cancers or mortality in IBD.22 PSC was diagnosed in 224 of 5506 patients with CD and 5522 with UC (2%). The overall cancer risk was increased in patients with versus without PSC (OR, 4.36; 95% CI, 2.99–6.37). In patients with IBD with PSC, a higher risk for gastrointestinal cancer, pancreatic cancer, and cholangiocarcinoma (OR [95% CI], 10.40 [6.86–15.76]; 11.22 [4.11–30.62]; and 5.00 [2.80–8.95], respectively) but not for hematologic malignancies was observed. Findings therefore supported that PSC is associated with increased risk of CRC and pancreatobiliary cancer.22

Hematologic Malignancies in IBD Patients Not Treated with Immunomodulators Since 1979, Greenstein et al23 reported an increased frequency of lymphoma in 1227 patients with CD. In 1982, Hanauer et al24 described development of leukemia in CD. Independent observations subsequently supported these findings. In 1984, an increased risk of intestinal lymphoma has been described in patients with CD not treated with immunomodulators.25 Since 1963,26 reports of intestinal lymphoma have also been described in UC. However, subsequent independent studies in patients with IBD lead to an established increased frequency of lymphoma only in CD. In 2011, a literature review in population-based long-term studies reported a slightly increased risk of lymphoma, irrespective of medication use.6 In 2012, an increased risk of primary intestinal lymphoproliferative disorders (PILD) has been observed in the CESAME French nationwide prospective observational


cohort.27 Among 19,486 patients with IBD (CD in 60.3%) PILD (all non-Hodgkin lymphoma [NHL]: B-cell LD) was detected in 14 patients (11 CD, 78.6% males, 45.5% EBV-positive). The incidence of PILD was 0.12/1000 pt-yrs (SIR 17.51; 95% CI, 6.43–38.11; P , 0.0001). The risk was highest in patients treated with thiopurines but not in patients thiopurines-naive or with ongoing exposure (versus naive) (SIR [95% CI], 49.52 [13.49– 126.8]; P , 0.0001; 4.83 [0.12–26.91]; P ¼ 0.37; 2.97 [0.30– infinity]; P ¼ 0.38).27

Immunomodulators and the Risk of Solid Tumors in IBD When considering the possible role of immunomodulators and/or anti-TNFs in the development of solid tumors in patients with IBD, the main findings are summarized in Tables 1 and 3, respectively. Among the first studies, Connell et al28 in 1994 evaluated the risk of neoplasia in 755 patients with IBD treated with azathioprine (AZA; 2 mg$kg21d21) (Tables 1 and 2). Overall, no significant excess of any cancer was observed: 31 patients treated with AZA versus 24.3 expected (ratio 1.27; P ¼ 0.186). However, a higher frequency of CCR13 and anal2 carcinoma was observed (expected 2.27; ratio 6.7; P ¼ 0.00001). In extensive UC, the frequency of CRC was comparable between matched patients treated or not treated with AZA (n ¼ 86 and n ¼ 180, respectively).28 In 1999, Korelitz et al29 reported in a single-center study, the frequency of cancer occurring over 27 years, in 550 patients with IBD treated with 6-mercaptopurine (6-MP; 12.5–100 mg/d), concluding that no neoplasm could be attributed to this treatment (Table 1). Neoplasms were observed in 25 patients (16 of 380 CD; 9 of 170 UC; P ¼ 0.66; incidence 2.7/1000 pt-yrs). Neoplasms were more frequently observed in the bowel (8 of 550, 1.6%: 5 CD, 3 UC) and breast (3, 0.5%: 2 CD, 1 UC). The incidence of CRC was comparable between patients treated with 6-MP and with longstanding colitis.29 In 2000, Farrell et al30 evaluated, in a single-center study including 238 patients with IBD treated with immunomodulators from 1990 to 1999, the risk of NHL and the association between IBD, NHL, and immunomodulators (Tables 1 and 2). In this cohort, a significantly higher risk of CRC, melanoma, and NHL was observed. In 2002, Fraser et al31 evaluated the relation between AZA treatment and cancer in IBD (Table 1), supporting that using AZA did not increase the cancer risk. Among 2204 patients with IBD, 626 were treated with AZA. Cancer occurred in a comparable proportion of patients treated or not with AZA (31 cancers in 30 patients [4.5%] versus 77 cancers in 70 patients [4.5%], respectively; P ¼ NS). In UC, CRC (including HGD) occurred in a comparable proportion of patients treated or not with AZA (8 of 355; 2.2% versus 28 of 994; 2.8%; P ¼ NS).31 When using biologics for IBD, the cancer risk in the longterm risk cannot currently be defined because the first trial using anti-TNFs in IBD (infliximab [IFX] in CD) has been published only in 1995.32 Moreover, the first trials using anti-TNFs included www.ibdjournal.org |

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a limited number of patients, and only subsequently combined treatment with thiopurines was widely used. In 2004, concern about the possible relationship between biologics and cancer was raised for the first time by Fiocchi33 in 1995. Rectal cancer indeed occurred in 2 patients with CD (2 men, 36 and 46 yr old), 24 months after the end of the ACCENT II trial.34 In 2006, the possible association between anti-TNFs use and cancer was addressed in a multicenter matched-control study including 808 patients with CD35 (Table 3). The frequency of any cancer was comparable between patients with CD treated (CDIFX, n ¼ 404) or not treated with IFX (CD-C, n ¼ 404), matched for clinical variables (cases: 9/404, 2.22% versus 7/40, 1.73%; P ¼ NS) (Tables 3 and 4). No specific cancer histotypes appeared to be associated with IFX use, although cases of CRC were observed in CD-C and in no CD-IFX patients (CCR versus total cancers: 2/7 versus 0/9, respectively).35 The same cohort of patients with CD was followed up for additional 4 years to assess the long-term cancer risk using IFX in CD. A comparable frequency of cancer was observed between IFX-treated (n¼304) and untreated patients in follow-up (3.94% versus 4.18%; P ¼ NS).36 No cases of CCR were observed in CD-IFX patients (versus 3 in CD-C), whereas lymphoma was observed in 1 CD patient per group (1 Hodgkin lymphoma [HL], 1 NHL).36 These preliminary observations have been confirmed and extended by several larger independent studies. In particular, the first report from the Treat Registry, published in 2006,37 supported, in a series of 6290 patients with CD, with 3179 treated with IFX (duration, 5519 pt-yrs; mean, 1.9 6 0.96 yr; median, 1.77 yr [range, 5–4.9], 87% $2 infusions) and 3111 others not treated with IFX (6123 pt-yrs) a comparable frequency of any cancer, including lymphoma, in patients treated or not with IFX. Malignancies leading to death were reported (including 1 peripheral T-cell lymphoma, 1 lung cancer, 1 renal cancer, and 1 CRC),37 In 2006, Bhatia et al38 (Table 3)38 evaluated the prevalence of abnormalities of the uterine cervix in 116 patients with IBD (64 CD, 52 UC) matched to 116 healthy controls (age 6 2 yr).38 Abnormal Pap smears were observed in a higher proportion of patients with IBD versus controls (18% versus 5%; P ¼ 0.004), whereas no differences were observed between patients with CD and UC, also in terms of immunomodulatory use (P ¼ 0.793). Findings supported that in women with IBD, there is an increased risk of abnormal Pap smear with no association with IBD type and immunomodulators use.38 Since 2007, several case-report, case-series, and monocentric studies investigated the possible relationship between anti-TNFs and overall cancer risk in IBD with no apparent correlation.39 In 2007, the first meta-analysis regarding this evaluated the risk of malignancy using immunomodulators in IBD (Tables 1 and 2).40 Findings from the 9 studies showed no difference (weighted mean difference [WMD], 20.3 · 1023 per pt-yrs; 95% CI, 21.2 · 1023 to 0.7 · 1023) in the incidence of any malignancy between both patients with IBD treated or untreated with immunomodulators and between CD and UC.40 In 2008, Caspersen et al41 (Table 3) in a single-center Danish cohort study including 651 patients with IBD treated with IFX

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reported that IFX use does not increase the risk of malignancy in IBD (cases: 4 versus 5.9 expected; SIR 0.7; 95% CI, 0.2–1.7) (Table 3).41 Accordingly, in 2008, Peyrin-Biroulet et al, in a meta-analysis including 21 placebo-controlled trials using IFX in CD (5356 patients treated), reported a comparable frequency of any cancer, including lymphoma, in patients treated with IFX. The authors however strengthened the need of larger studies and longer follow-up periods (Table 3).42 In 2008, Kane et al43 (Table 1) in a single-center study, evaluated 40 patients with IBD (8 UC, 32 CD) with 134 Pap smears, to assess the relationship between immunomodulators and abnormal cervical histology in IBD (Table 1). A higher incidence of any abnormal Pap and higher grade lesions were observed in patients with IBD versus controls (42.5% versus 7%; P , 0.001), particularly in IBD woman assuming immunomodulators (P , 0.001). The use immunomodulators for .6 months further increased this risk (OR, 1.5 [1.2–4.1]; P ¼ 0.021). HPV serotype 16 or 18 was detected in all specimens. In 2009, Fidder et al44 in a retrospective analysis in a singlecenter cohort study, reported a comparable rate of malignancies in patients with IBD treated (n ¼ 734) or untreated with IFX (n ¼ 666) (2.8%, 100 pt-yrs 0.4 versus 4.5%, 100 pt-yrs 0.5; P ¼ NS) (Table 3). Diagnosis of cancer occurred at younger age in patients treated with IFX versus controls (median [range], 42 [23–73] yr versus 55 [34–87] yr; P , 0.01). In this cohort, CRC occurred only in patients never treated with IFX (8/66; 1.2% versus 0/734, 0%) (Table 3) as in a previous multicenter study.35 In animal models of colitis, blocking TNFs using etanercept may reduce the colitisassociated colorectal carcinogenesis.4 A possible role played by anti-TNFs in humans may be speculated, although evidences in humans are currently lacking.45 Moreover, growing evidences also suggest a role for anti-inflammatory treatments, including mesalazine and AZA, for preventing CRC associated with chronic inflammation in IBD colitis.46 In 2009, a population-based, nested, case-control study, evaluated the risk of cervical abnormalities in 9692 women with IBD and cervical cytologic and/or histologic abnormalities. Patients with IBD were matched with 57,898 IBD controls with normal Pap smears (Table 1).47 No association between cervical abnormalities and UC was observed (OR, 1.03; 95% CI, 0.77–1.38). However, the combined corticosteroids and immunomodulators treatment was associated with increased risk of cervical abnormalities (OR, 1.41; 95% CI, 1.09–1.81).47 In 2010, Armstrong et al48 examined, in a nested casecontrol study, the possible relation between AZA use and cancer in IBD (Table 1). Overall, cancer occurred in 392 of 15,471 patients with IBD, including 10.5% in patients treated with AZA (versus controls: 1914; 12.7%). No increased cancer risk in patients with IBD treated with AZA was observed, thus suggesting no need to discontinue AZA in relation to the risk of malignancy.48 In 2010, Long et al,49 in a retrospective cohort and nested case-control studies evaluated the risk of NMSC in IBD and how immunomodulators and anti-TNFs affect this risk (Table 3). In this cohort study, each CD (n ¼ 26,403) and UC patient (n ¼ 26,974) was matched to 3 non-IBD controls. The incidence of NMSC was higher in IBD (IRR, 1.64; 95%


CI, 1.51–1.78). The nested case-control study included 387 patients with CD and 355 UC with NMSC, each matched to 4 patients with IBD without NMSC. Recent (#90 d) thiopurine and anti-TNFs use was associated with NMSC (OR, [95% CI], 3.56 [2.81–4.50] and 2.07 [1.28–3.33], respectively). Persistent (.365 d) thiopurine and anti-TNFs use was associated with NMSC in CD (OR [95% CI], 4.27 [3.08–5.92] and 2.18; [1.07– 4.46], respectively). Findings supported that patients with IBD, especially those treated with thiopurines, are at risk for NMSC, thus indicating the need of appropriate dermatologic screening, counseling, and monitoring of treated.49 The comparable frequency of any cancer in patients treated or not with anti-TNFs was also supported in 2011 by a multicenter IG-IBD study from Cottone et al50 In this multicenter study, older (.65 yr) patients with IBD treated with IFX (n ¼ 2475) or adalimumab (n ¼ 604) showed a comparable malignancy rate between patients treated or not with anti-TNFs (3% versus 2%; P ¼ NS).50 In 2011, Peyrin-Biroulet et al51 compared, in a prospective observational cohort study, the risk for NMSC in 19,486 patients with IBD treated with thiopurines versus the general population (Table 1). Findings supported that ongoing thiopurine (HR, 5.9; 95% CI, 2.1–16.4; P ¼ 0.0006) and past thiopurine exposure (HR, 3.9; 95% CI, 1.3–12.1; P ¼ 0.02) increases the risk of NMSC in patients with IBD, even before the age of 50 years. The authors therefore suggest protection against UV radiation and lifelong dermatologic screening for patients with IBD treated with NMSC.51 In 2011, Singh et al52 supported these findings, reporting an increased risk of NMSC in patients with IBD and particularly in those treated with thiopurines (Table 1). In a cohort of 9618 patients with IBD, 1696 were diagnosed with basal cell skin cancer (BCC) and 341 with squamous cell skin cancer. Patients with IBD had an increased risk for BCC versus controls (HR, 1.20; 95% CI, 1.03–1.40). In IBD, thiopurines use increased the risk of squamous cell skin cancer (HR, 5.40; 95% CI, 2.00–14.56) as also supported in a case-control nested analysis of patients with IBD (OR, 20.52; 95% CI, 2.42–173.81).52 In 2011, this observation was not supported by Van Schaik et al53 reporting, in a population-based study including 819 patients with IBD, no increased risk of NMSC in patients with IBD treated with thiopurines (HR, 0.85; 95% CI, 0.51–1.41). In 2012, Long et al14 in a retrospective cohort and nested case-control study assessed the risk of melanoma and NMSC in patients with IBD (Table 3). In the cohort study, 108,579 patients with IBD were each matched to 4 subjects without IBD. In nested case-control studies, patients with melanoma or NMSC were matched to 4 patients with IBD without melanoma or NMSC. The study showed an increased incidence of melanoma, particularly in CD (IRR, 1.29; 95% CI, 1.09–1.53 and IRR, 1.45; 95% CI, 1.13–1.85; adjusted HR, 1.28; 95% CI, 1.00–1.64). The incidence of NMSC also was higher in IBD, particularly in CD (IRR, 95% CI, 1.46; 1.40–1.53 and 1.64; 1.54–1.74). Biologics increased the risk of melanoma (OR 1.88; 95% CI, 1.08–3.29). Thiopurines increased the risk of NMSC (OR, 1.85; 95% CI, 1.66–2.05). Findings supported that biologics increase the risk of melanoma and


thiopurines the risk of NMSC.14 In 2012, Lichtenstein et al54 analyzed the safety of long-term use of IFX, with or without concomitant immunomodulators, in 10 CD and 5 UC randomized, controlled trials including patients treated with IFX (n ¼ 1713; 6AZA) or placebo (n ¼ 406; 6AZA).54 In IBD, no increase in malignancy was observed in trials using IFX versus placebo. In placebo-treated patients with CD, but not UC, immunomodulator use showed a higher incidence of malignancy (1.84 [0.22–6.66]/ 100 pt-yrs versus 0.00 [0.00–0.00]/100 pt-yrs).54 In 2012, a singlecenter cohort study evaluated the relationship between cancer, severity of IBD, and use of immunmodulators in patients with CD (n ¼ 615) and with UC (n ¼ 607).17 Findings indicated fistulizing pattern in CD and pancolitis in UC but not immunomodulators as independent risk factors for cancer in IBD. The incidence of cancer did not differ between patients with CD with or without immunomodulators and/or anti-TNFs (1000 pt-yr: CD never treated with either treatment: 3.5; CD treated with immunomodulators; 3.8: P ¼ 0.81; CD treated with anti-TNFs: 2.7; P ¼ 0.93; CD treated with both treatments: 3.4; P ¼ 0.9). Immunomodulators did not affect the incidence of cancer in UC (2.4/1000 pt-yr versus 2.5/ 1000 pt-year; P ¼ 0.91). The incidence of cancer in patients with UC with no anti-TNFs was 3.1/1000 pt-year (95% CI, 1.9–5 per 1000 pt-yr), whereas no cases of cancer were observed in patients with UC treated with anti-TNFs, most likely because of the limited number of treated patients (n ¼ 46). In this cohort, neither immunomodulators nor anti-TNFs appeared to be associated with cancer risk in both CD and UC (P ¼ 0.44 and P ¼ 0.13).17 In 2013, Jess et al,18 in a population-based study, evaluated cancer risk in a well-characterized population-based IBD cohort from Denmark (Table 1). In a cohort of patients with IBD (1515 UC, 810 CD), patients with UC showed no overall increased risk of cancer (SIR, 1.12; 95% CI, 0.97–1.28) but an increased risk of prostate cancer (SIR, 1.82; 95% CI, 1.17–2.71). Patients with CD showed a 55% increased cancer risk overall (SIR, 1.55; 95% CI, 1.29–1.84) related to young age, colonic disease, smoking, and thiopurines use. Patients with CD showed an increased risk of SBC, lung cancer (associated with female gender and smoking), CCR in males, cervical dysplasia (associated with young age at diagnosis, smoking, 5-ASA and thiopurines), and NHL (unrelated to thiopurines) (SIR [95% CI], 15.18 [1.84–54.78]; 2.13 [1.19– 3.52]; 2.43 [1.05–4.78]; 1.65 [1.10–2.37]; 3.43 [1.38–7.07]). The authors concluded that patients with CD but not UC have an overall excess risk of cancer and that clinical characteristics of patients with IBD at excess risk differ by cancer subtype.17,55 In 2013, Pasternak et al,55 in a cohort study, compared rates of overall incident cancer and cancer subgroups between patients using AZA or not (5197 [11%] of 45,986 patients with IBD treated with AZA) (Table 1). Overall, 2596 incident cases of cancer were detected. AZA use, but not former use, was associated with an increased cancer risk (relative risk [RR] ¼ 1.41; 95% CI, 1.15– 1.74 and RR ¼ 1.02, 95% CI, 0.83–1.25, respectively). However, no causality could be established. In 2014, a systematic review by Williams et al56 with metaanalysis pooled data from all available placebo-controlled studies www.ibdjournal.org |

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estimated the risk of malignancy using anti-TNFs in IBD (22 randomized controlled trials involving 7054 patients: 4566 CD, 2488 UC) (Table 3). Malignancies were observed in a comparable proportion of patients treated with anti-TNFs or randomized to placebo (16 of 4135; 0.39% versus 13 of 2919; 0.45%). The RR of malignancy for patients treated with anti-TNFs versus placebo was 0.77 (95% CI, 0.37–1.59), although it is concluded that an increased risk beyond 1 year of treatment could not be excluded as no trials provided this information.56 In 2014, Lichtenstein et al57 assessed, in the TREAT Registry, potential associations between malignancy and anti-TNFs in CD (Tables 3 and 4). The study included 6273 patients with CD (IFX during or #1 yr before registry, n ¼ 3764; other treatments-only: n ¼ 2509; mean follow-up: 5.2 and 7.6 yr, respectively). Cancer incidences were comparable between patients exposed only to IFX and patients exposed to other treatments but not to IFX. Neither immunomodulators alone, IFX alone, nor their combination (HR, 1.43; P ¼ 0.11; 0.59; P ¼ 0.16; 1.22, P ¼ 0.34) were independently associated with the risk of malignancy. The incidence of any malignancy was comparable with the general population. Neither immunomodulators alone (OR, 4.19) nor in combination with IFX (OR 3.33) increased the risk of malignancy versus IFX use alone (OR 1.96). It is concluded that although results for immunomodulators were equivocal, no significant association between malignancy and IFX was observed.57 In 2014, Ariyaratnam et al58 in a metanalysis including 8 studies involving 60,351 patients, the association between thiopurine use and NMSC in IBD (Table 1). The pooled adjusted HR of developing NMSC after thiopurines in IBD was 2.28 (95% CI, 1.50–3.45). The risk of NMSC was higher in hospital-based versus population-based studies (HR [95% CI], 7.11 [2.08–16.90] versus 1.83 [1.2–2.8]). The pooled adjusted HR was higher for studies with shorter follow-up (,3 yr) than for studies with longer duration (.6 yr) (2.87 [95% CI, 2.02–4.08] versus 1.88 [95% CI, 0.87–4.06]).59 In 2014, Osternan et al59 determined the RR of malignancy in patients with CD treated with adalimumab versus the general population and in patients with CD using combination adalimumab and immunomodulators versus adalimumab monotherapy (Table 3). A pooled analysis of data from 1594 patients with CD included in clinical trials of adalimumab was performed. Patients receiving combination therapy but not patients treated with adalimumab monotherapy had a greater incidence of malignancies other than NMSC (SIR 3.04; 95% CI, 1.66–5.10) and of NMSC (SIR, 4.59; 95% CI, 2.51–7.70). Patients treated with combination therapy also showed an increased risk of malignancy other than NMSC (RR, 2.82; 95% CI, 1.07– 7.44) and of NMSC (RR, 3.46; 95% CI, 1.08–11.06). Therefore, in CD, adalimumab monotherapy does not increase the incidence of malignancy, whereas combined immunomodulators and adalimumab use increased the risk of NMSC and other cancers.59 In 2014, Singh et al60 investigated the risk of melanoma in IBD in a systematic review and meta-analysis of 12 cohort studies including 172,837 patients with IBD (Table 3). Melanoma was detected in 179 patients with IBD, and the pooled crude incidence rate was 27.5 cases/100,000 pt-yrs (95% CI, 19.9–37.0). IBD was associated with a 37% increase in risk of melanoma (RR, 1.37; 95% CI, 1.10–

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1.70), and the risk was increased in both CD and UC (RR, 1.80; 95% CI, 1.17–2.75 and RR, 1.23; 95% CI, 1.01–1.50, respectively). The higher melanoma risk was observed only in studies performed before the use of biologics in IBD (1998) (RR, 1.52; 95% CI, 1.02–2.25) and not in studies performed after 1998 (RR, 1.08; 95% CI, 0.59–1.96). Findings therefore suggested that IBD is associated with an increased melanoma risk not related to the use of biologics, thus supporting the need of a proper follow-up related to this risk.60 On the basis of these findings, an ECCO workshop in 201461 reported that patients with IBD treated with immunosuppressants bear an increased risk of skin cancers, particularly of NMSC in patients treated with thiopurines, while a mild increased risk of melanoma in those treated with anti-TNFs. A program of sun protection and dermatological surveillance is therefore recommended for patients with IBD particularly in those treated with thiopurines and biologics.21,61

Immunomodulators and Risk of Hematologic Malignancies in IBD CD bears an increased risk of lymphoma, even in patients never treated with thiopurines and/or anti-TNFs.23–25 Since 1989, growing studies suggest the possible relationship between thiopurines use in CD and risk of lymphoma.62 The main findings regarding the risk of lymphoma using thiopurines in CD are summarized in Table 2. In 1994, Connell et al28 reported the risk of neoplasia after AZA therapy in 755 patients treated for IBD, reporting only 1 case of lymphoma (HL) (expected 0.52; P ¼ 0.69) (Table 2). In 1999, Korelitz et al29 in a single-center study reported that among 550 patients with IBD (380 CD, 170 UC) treated with 6-MP (12.5–100 mg/d), hematologic malignancies occurred in 3 of 380 patients with CD. Malignancies in CD included 2 NHL (1 cerebral, 1 abdominal) and 1 leukemia. Findings supported that although no cases of neoplasms could be attributed to 6-MP, suspicion of a relationship between 6 MP and hematologic malignancies was not excluded. In 2000, Lewis et al62 analyzed, using a Markov model, the benefit and risks, including lymphoma risk, when using AZA in CD. In patients with CD with steroid-induced remission, using AZA determined an average increase in life expectancy of 0.04 years and 0.05 quality-adjusted years. This increase was greater in young patients, showing the lowest baseline risk of NHL and the greatest life expectancy in case of no CD-related death.63 In 2000, Farrell et al,30 in a single-center study, evaluated the risk of NHL in a large cohort of patients with IBD. IBD population included 782 patients (238 treated with immunomodulators). NHL (3 intestinal, 1 mesenteric) occurred in 4 patients (3 UC, 1 CD) treated with immunomodulators: AZA (n ¼ 2), methotrexate (MTX; n ¼ 1), or MTX and CyS (n ¼ 1). Patients with IBD treated with immunomodulators had a (59 times) higher risk of NHL than the general population (P ¼ 0.0001) (Table 2). The authors concluded that although underlying IBD may be a causal factor in the development of intestinal NHL, immunomodulators can significantly increase the risk of NHL.30


In 2001, Lewis et al64 examined the risk of HL and NHL in IBD. In a population-based retrospective cohort study, lymphoma rates were assessed in 6605 patients with CD, 10,391 with UC, and 60,506 controls. Overall, 1465 patients with IBD were treated with thiopurines. The incidence of lymphoma was not increased in IBD, CD, or UC (RR [95% CI], 1.20 [0.67–2.06], 1.39 [0.50–3.40], 1.11 [0.51–2.19], respectively). However, the RR of lymphoma among the 1465 patients with IBD treated with thiopurines (average, 106 mg/d for 2.0 yr) was 1.27 (95% CI, 0.03–8.20). Data supported that although the lymphoma risk was not increased, a modest increased risk using thiopurines cannot completely be ruled out.64 In 2002, Freeman65 tabulated myeloid and lymphoid malignancies in 1000 consecutive patients with CD followed up over an extended period by a single clinician. Immunomodulators were used by 117 patients with CD (99 AZA, 7 CyA, and 11 MTX) and biologics by 5 patients. Myeloid and lymphoid neoplasms occurred in 0.5% (4 of 883 patients not treated with immunomodulators). Most of these patients had a long-term (.20 yr) and severe CD. No cases of lymphoma were reported, possibly because of the limited use of immunomodulators or anti-TNFs in the study.65 In 2002, the possible relation between lymphoma and EBV in IBD was evaluated at a single tertiary center considering cases of lymphoma diagnosed between 1985 and 2000.66 Findings were considered in 2 periods of 8 years each (1985–1992, 1993– 2000), corresponding with the introduction of AZA and 6-MP in 1993. Lymphoma was observed in 18 patients (6 between 1985 and 1992, 12 between 1993 and 2000): thiopurines were used by 6 of the 18 patients with lymphoma. EBV-positive lymphoma was observed in 7 patients, occurring more frequently in patients treated with thiopurines (5/7; P ¼ 0.01). Findings supported that using thiopurines in IBD appears to be associated with a small increased risk of EBV-positive lymphoma.67 Fraser et al31 in 2002, in a retrospective review, evaluated the risk of malignancies using AZA in IBD, concluding that AZA does not increase the risk of any cancer. The study included 2204 patients with IBD, including 626 treated with AZA (Table 2). The mean follow-up from the diagnosis of IBD was 13.7 years. Lymphoma was observed in 8 patients with CD: 3 of them were treated with AZA (P ¼ NS).31 In 2005, a meta-analysis from Kandiel et al67 including 5 studies, supported that in patients with CD treated with thiopurines, there is a 4-fold increased lymphoma risk (Table 2). The overall SIR for the risk of lymphoma using thiopurines was 4.18 (2.07–7.51), although a significant heterogeneity was observed among studies (SIR, 0–37; 95% CI, 3.5–137.7; P ¼ 0.03). Overall, 11 cases of lymphoma were observed (expected 2.63). The incidence rates from 1996 to 2000 were higher in older patients with IBD (7.65 for 20–29 yr versus 93.90 for 70–79 yr).68 The NNH to cause 1 additional lymphoma per year showed wide variations in relation to patients’ age and to the RR (age 20–29 versus 70–79: 13,072 versus 1065 for RR 2; 4357 versus 355 for RR 4; 2614 versus 213 for RR 6).68 In 2006, Siegel et al69 constructed a decision analytic model to determine the risks and benefits of IFX versus standard therapy. The analysis simulated 2 cohorts of 100,000 patients: one arm on IFX and the other on standard therapy. According to this model,


in 100,000 pt-years, IFX will lead to 12,216 more patients in remission, 4255 fewer surgeries, and 33 fewer deaths from CD flares. However, the benefits of using IFX will occur at the cost of 201 more lymphomas and 249 more deaths due to IFX complications. As the use of IFX determined a more QoL years than the standard therapy, findings supported that in properly selected patients with CD, the benefits of IFX could outweigh its risks.68 In 2007, Masunaga et al40 in a meta-analysis including 9 cohort studies, evaluated the risk of malignancy using immunomodulators in IBD (Tables 1 and 2). Findings supported that the use of immunomodulators in CD or UC probably does not confer a significantly increased risk of malignancy. The incidence of any malignancy in patients with IBD treated or not with immunomodulators indeed showed no discernible difference (WMD 20.3 · 1023 per pt-yrs; 95% CI, 21.2 · 1023 to 0.7 · 1023), being comparable between CD and UC. The WMD for lymphoma in 3791 patients with IBD was 0.0 (95% CI, 20.8 to 0.7) and for leukemia 20.1 (95% CI, 20.4 to 0.3).40 In 2008, Caspersen et al41 in a single-center Danish study reported no hematologic malignancies among 651 patients with IBD (619 CD, 15 UC, 17 colitis unclassified) treated with IFX from 1999 to 2005, as observed for solid tumors (Table 3). In 2009, a meta-analysis from Siegel et al70 evaluated the risk of lymphoma associated with combination anti-TNFs and immunomodulators for CD (Table 4). The meta-analysis included 26 studies considering 8905 patients (21.278 pt-yr per follow-up). Findings from 9 randomized controlled trials, 3 cohort studies, and 14 case series were considered. SIR was calculated by comparing the pooled NHL rate from anti-TNFs studies with population-based NHL rates from 2 sources: the SEER cancer registry (No IBD: 1.9/10.000 pt-yrs) (ref) and a meta-analysis of patients with CD treated with thiopurines (CD with thiopurine alone: 3.6/10.000 pt-yrs).68 Overall, 13 NHL were observed among 8905 CD (6.1/10.000 pt-yr), and immunomodulators were used by 10 of these 13 patients (12 thiopurines, 1 MT). The rate of NHL per 10,000 pt-yrs was 1.9 versus SEER, 3.6 versus the Kandiel metaanalysis,67 6.1 for anti-TNFs versus SEER (SIR, 3.23; 95% CI, 1.5– 6.8) and 6.1 for anti-TNF versus immunomodulators alone (SIR 1.7; 95% CI, 0.5–7.1). When the analysis was restricted to young male patients (age 20–54 yr), a higher risk of NHL using anti-TNFs was observed (SIR, 5.4; 95% CI, 1.3–18.1). Overall, findings supported that anti-TNFs with immunomodulators induce an increased risk of NHL, although the absolute rate of these events is low and should be weighed against the benefits associated with their use.70 In 2009, Beaugerie et al71 in a prospective population-based study including 19,486 patients with IBD (61% CD; 39% UC/ colitis unclassified) addressed the risk of PILD in patients with IBD treated with thiopurines (Table 2). Among these 19,486 patients with IBD, 30% of patients were receiving (n ¼ 5867), 14% discontinued (n ¼ 2809), and 56% never received immunomodulators (n ¼ 10,810). The incidence rates of PILD were higher in patients receiving versus those who discontinued or never used immunomodulators (rates 1000 pt-yr [95% CI], 0.90 [0.50–1.49] versus 0.20 [0.02–0.72] versus 0.26 [0.10–0.57], respectively www.ibdjournal.org |

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P ¼ 0.0054). The yearly incidence rate was significantly higher in patients .65 years.72 In 2009, a review from Sokol including single-center and population-based studies concluded that in IBD, the role played by immunomodulators in lymphomagenesis is difficult to individualize because other factors potentially involved are interlinked.72 Overall, 11 population-based studies were included, showing an OR ranging for CD from 0.0 (0.0–2.4) to 2.4 (1.2–5.0) and for UC from 0.0 (0.0–6.4) to 1.8 (0.2–6.5). The authors also suggested the need to quantify the probably low risks of fatal postmononucleosis LD and of hepatosplenic T-cell lymphoma in young male patients treated with combined anti-TNFs and immunomodulators, and respectively, EBV-seronegative males.72 In 2010, Armstrong et al48 in a nested case-control study compared AZA use between patients with (IBD cases) or without a diagnosis of cancer (IBD controls). The study population included 15,471 patients with IBD: 392 developed cancer (10.5% received $1 prescription for AZA versus 12.7% of the controls). Lymphoma was associated with ever use of AZA (OR, 3.22; 95% CI, 1.01–10.18). Findings supported an increased lymphoma risk but not overall increase cancer risk in patients with IBD treated with AZA, and it is therefore concluded that the cancer risk does not require the need for AZA cessation in the medium term.48 In 2011, Herrinton et al73 compared the incidence of lymphoma between the IBD cohort 1996 to 2009 and the general population. The study included 16,023 patients with IBD treated with thiopurines (24%), IFX (7%), or adalmumab (2%) (thiopurines or anti-TNFs: 21,282 pt-yr: 81% thiopurines, 3% anti-TNFs; and 16% combined). Lymphomas occurred in 43 patients with IBD (0.26%; HD 12%; N ¼ 5). The frequency of lymphoma was higher in men and in younger patients (P , 0.0001 age #44 versus .44 year old). Findings supported that: (1) IBD is not associated with an increased lymphoma risk, (2) the risk is increased by the combined anti-TNFs and thiopurines or by current use of thiopurine alone, (3) even with combination therapy, lymphoma risk is low (age-SIR: 113.8/100.000 pt-yrs). It is concluded that the effect of IBD severity merits further evaluations.73 Regarding this, in 2012, a single-center cohort study investigated whether clinical characteristics of IBD are independent risk factors for cancer, when considering thiopurines and anti-TNFs use.17 The incidence rate of cancer in IBD was 51/1222 (4.3/1000 pt-yr) in CD 34/615 (4.6/1000 pt-yr) and in UC 17/607 (2.9/1000 pt-yr; P ¼ NS versus CD). In CD, the incidence rate of cancer was higher in patients with fistulizing (9.3/1000 pt-yr) versus inflammatory (3.8/1000 pt-yr; P ¼ 0.03) or fibrostricturing (2.4/1000 pt-yr; P ¼ 0.0012) disease. In UC, the incidence rate of any cancer was higher in pancolitis (6.8/1000 pt-yr) versus distal (2/1000 pt-yr; P ¼ 0.015) or subtotal (3.4/1000 pt-yr; P ¼ 0.045) disease.17 In this single-center study, fistulizing pattern in CD, pancolitis in UC, and older age at diagnosis of IBD seemed to be independent risk factors for cancer.17 In 2013, Jess et al18 (Table 1) in a population-based study, evaluated cancer risk in a population-based IBD cohort from Denmark. At this purpose, 1515 patients with UC and 810 patients with CD with a diagnosis of IBD made from 1978 to 2002 were followed until December

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31, 2010 for occurrence of incident cancer. Patients were at increased risk of NHL (SIR, 3.43; 95% CI, 1.38–7.07, unrelated to thiopurines) and of other solid tumors. Findings supported that patients with CD, but not UC, have an overall excess risk of cancer and that clinical characteristics of patients with IBD at excess risk differ by cancer subtype.18 In 2012, Sokol et al27 investigated whether IBD is associated with an increased risk of PILD in 19,486 patients with IBD (CD in 60.3%) included in the CESAME population (Table 2). Patients with IBD were subgrouped according to thiopurines use (ongoing, discontinued, and never; UC group, n ¼ 1,415, 655, and 5657 patients; CD group, n ¼ 4452, 2154, and 5153 patients, respectively). The incidence of PILD was 0.12/1000 pt-yrs (SIR, 17.51; 95% CI, 6.43–38.11; P , 0.0001). PILD occurred in 14 patients (11 with CD; 3 with UC). The risk was the highest in thiopurines-treated patients, whereas it was not significant in thiopurines-naive patients (SIR [95% CI], 49.52 [13.49–126.8]; P , 0.0001; 4.83 [0.12–26.91]; P ¼ 0.37). The OR associated with current thiopurine exposure (versus naive) was 2.97 (P ¼ 0.38). All 14 cases of PILD were NH B-cell LD, (78.6% males, 85.7% in IBD lesions, 5.5% EBV-positive). Findings supported that patients with IBD have an increased risk of developing PILD.74 In 2012, Siegel et al74 constructed a decision model to compare the risks and benefits of IFX/AZA with IFX monotherapy. According to this model, during 1 year, the benefits of IFX and AZA would outweigh the risks, unless lymphoma occurred in 3.9% or more of the population, being 65-fold higher than base-case estimates. The authors concluded that the incidence of severe adverse events would have to be higher than clinically realistic for the risks of combo therapy to outweigh the benefits.74 In 2012, a single-center cohort study reported the occurrence of NHL in 1 of 105 patients with CD treated with AZA and in none of the 63 patients with UC treated with AZA.17 One case of HL occurred in 1 of the 500 patients with CD never treated with AZA.17 In 2013, Siegel et al75 reviewed articles regarding associations between immunomodulators and malignancies in IBD and other diseases, concluding that thiopurines and anti-TNFs increase the risk of lymphoma (particularly NHL) in IBD. Thiopurines and anti-TNFs use were also associated with an increased frequency of a rare hepatosplenic T-cell lymphoma (HSTCL) in IBD, particularly young male patients with CD, and with high rates of NMSC (below reported). A possible increased risk of melanoma using anti-TNFs and abnormal cervical cytology in female patients with IBD treated with immunomodulators was suggested. Findings, however, supported that the absolute rates of these malignancies remain low, and these risks should be weighed against the efficacy of thiopurines and anti-TNFs.75 In 2013, Khan et al76 evaluated, in a retrospective cohort study, the risk of lymphoma among thiopurine-treated patients with UC (Table 4). By reviewing data on 36,891 patients (median follow-up, 6.7 yr), thiopurines were used by 4734 patients with UC (13%). In patients with UC not treated, treated, and who discontinued thiopurines, lymphoma developed in 119, 18, and 5 patients, respectively (incidence rates 1000 pt-yr: 0.60, 2.31,


and 0.28). Findings supported that patients with UC have a 4-fold increase in risk of lymphoma during thiopurines treatment, and that the risk increases with the duration of treatment, thus indicating that discontinuing thiopurines reduces the lymphoma risk.76 In 2013, Jess et al,18 in a population-based study from Denmark (Table 2) reported that patients with CD had a 55% increased risk of cancer overall related to thiopurines and of NHL unrelated to thiopurines (SIR [95% CI], 1.55 [1.29–1.84] versus 3.43 [1.38–7.07], respectively).18 In 2013, Afif et al69 evaluated, in a case-control study, risk factors for lymphoma in IBD. At this purpose, adult patients with IBD (n ¼ 80) who developed lymphoma between 1980 and 2009 were matched with 2 controls. Lymphoma occurred in men in 60 of the 80 cases, (75%) (versus controls: 77, 48%), at a median age of 59 years (versus controls: 42). Immunomodulators were used by 20 patients with lymphoma (25%) and by 23 controls (14%), whereas anti-TNFs were used by 5 patients (5%) and 6 controls (4%). Increased risk of developing lymphoma was associated with age, male gender, and immunomodulators (OR [95% CI], 1.83 [1.37–2.43]; 4.05 [1.82–9.02]; 4.20 [1.35–13.11], respectively). IBD severity and anti-TNFs use were not independently associated with lymphoma. EBV was identified in 75% of patients treated with immunomodulators or anti-TNFs. Findings supported that increasing age, male gender, and immunomodulators were associated with an increased lymphoma risk in IBD.69 In 2013, Pasternak et al55 in a cohort study of 45,986 patients with IBD (5197 [11%] treated with AZA) evaluated incident cancer rates between patients using and not using AZA (Table 2). Overall, 2596 incident cases of cancer were detected: AZA use was associated with an increased overall cancer risk (RR ¼ 1.41; 95% CI, 1.15–1.74). Differently, former use (RR ¼ 1.02; 95% CI, 0.83–1.25) or increasing cumulative doses of AZA were not. AZA was associated with increased risk of lymphoid tissue and urinary tract (RR [95% CI], 2.40 [1.13– 5.11] and 2.84 [1.24–6.51], respectively). A high frequency of genitourinary cancer in IBD has also been reported in preliminary findings from a prospective multicenter study.77 Findings from Pasternak et al55 supported that although AZA use was associated with an increased overall cancer risk in IBD, no causality can be established. In 2013, Lakatos et al78 analyzed the incidence of lymphomas in relation to immunomodulator treatments, in a population-based database including 1420 incident cases (Table 4). Among the 1420 patients (UC 914; CD 506), 3 developed lymphoma (1 CLL, 2 low-grade B-cell NHL including 1 rectal case). All 3 patients were male, and none had a history of AZA or antiTNFs. The absolute incidence rate of lymphoma was 1.55/10,000 pt-yrs, with 3 cases observed versus 2.18 expected (SIR, 1.37; 95% CI, 0.44–4.26). Findings supported no increased lymphoma risk in IBD and no association with thiopurine use.78 In 2014, the risk of myeloid disorders was prospectively evaluated in a large French cohort of patients with IBD (Table 4).79 The study included 19,486 patients with IBD enrolled in the CESAME study, compared with the general population. Incident myeloid disorders were observed in 5 patients (2 acute myeloid leukemia, 3 myelodysplastic syndromes: 4 patients treated with


thiopurines). No increased risk of myeloid disorders was observed, when considering patients with IBD either versus the general population and treated with thiopurines (SIR [95% CI], 1.80 [0.58– 4.20]; 1.54 [0.05–8.54], respectively). Differently, patients with IBD with past thiopurines use had an increased risk of myeloid disorders (SIR, 6.98; 95% CI, 1.44–20.36) and showed a 7-fold increased risk of myeloid disorders.79 In 2014, a systematic review from Williams et al56 with meta-analysis reported data from all available placebo-controlled studies to estimate malignancy risk using anti-TNFs in IBD (Table 4). Overall, 22 randomized controlled trials using anti-TNFs (11 IFX, 6 adalimumab, 4 certolizumab, 1 golimumab) and involving 7054 patients (4566 CD, 2488 UC) were included. Lymphoma was observed in no patients from the anti-TNFs group and in 3 (0.1%) patients in the control group. The RR of malignancy with anti-TNFs versus placebo including trials of $8-week duration was 0.80 (95% CI, 0.37–1.73). No effect of concomitant immunosuppressant use on risk of malignancy was observed. Anti-TNFs use therefore appeared not to be associated with an increased malignancy risk in IBD, although no information is available regarding the risk beyond 1 year of treatment.56 In 2014, Kotlyar et al80 assessed, in a meta-analysis considering 18 referral center and population-based studies, the risk of lymphoma in patients with IBD treated with thiopurines. An increased risk of lymphoma in patients with IBD taking thiopurines ($1 yr) was observed (SIR, 4.49; 95% CI, 2.81–7.17). This increased risk was lower in population studies (n ¼ 8) versus referral studies (n ¼ 10) (SIR [95% CI], 2.43 [1.50–3.92] versus 9.16 [5.03–16.7]), particularly after thiopurine discontinuation (1.42 [0.86–2.34] versus 5.71 [3.72–10.1] in current users). A greater risk was observed in male patients (RR ¼ 2.05; P , 0.05) and in younger patients (#30 yr: SIR, 6.99; CI, 2.99–16.4), although the absolute risk was the highest in older patients ($50 yr: 1:377 cases per pt-yr).81 In 2014, an ECCO workshop referred that in IBD patients, LD in developed countries shows an increased incidence and that thiopurines represent an additional risk of 3 forms of LD: EBV-related posttransplant-like LD, HSTCL, and postmononucleosis LD.21

Immunomodulators and Risk of HSTCL HSTCL is a rare lymphoma, associated with a severe and often fatal course, particularly in male patients.81 Since 2007, this rare lymphoma became well known by the IBD scientific community, due to growing reports of HSTCL in patients with IBD treated with immunomodulators. A worldwide warning derived from these preliminary observations, and attempts have been made to search for possible risk factors of HSTCL. In 2007, a preliminary report described the development of 8 cases of HSTCL in patients with IBD treated with IFX from 1998 to October 6, 2006.82 As confirmed by subsequent observations, HTSCL using immunomodulators in IBD was mainly observed in males (7 of 8 cases), patients with CD (7 CD 1 UC), at young age (all #31 yr), treated with combined thiopurines and anti-TNFs (all 8 patients), being associated with a poor prognosis (death in 7 of 8 cases).82 The relationship between HSTCL and IBD has been further supported by a review from Tai et al83 indicating that among the overall 200 cases reported www.ibdjournal.org |

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on 2010, 72% of cases developed “de novo,” 18% in immunocompromised patients, and 10% after treatments for IBD. As suggested by the first 8 cases of HSTCL reported in IBD, characteristics of the first 22 cases also supported a significant association with CD, male gender (21 of 22), young age, and poor outcome. However, a more significant association between HSTCL and thiopurines (all 22 patients) versus anti-TNFs use (14 of 22 patients) emerged.83 In 2010, Kotlyar et al84 reported that among the overall 100 to 200 cases of HSTCL described at time of publication,84 36 were observed since 1996: 32 of these 36 cases were observed since 2006, all 36 patients received thiopurines and 20 patients received combined thiopurines and anti-TNFs (20 IFX, followed by adalimumab in 4; natalizumab in 1). Among these 36 cases, HSTCL developed after combined treatment in 16 and after thiopurines only in 11: at time of publication, 27 deceased due to HSTCL. No cases of HSTCL were observed in patients with IBD treated with anti-TNFs and no thiopurines. Among anti-TNFs, 4 patients were treated with both IFX and adalimumab, together with a thiopurine, whereas 1 patient was treated with IFX, adalimumab, and natalizumab. Male gender and young age were more common in patients with HSTCL (2 females among the 31 patients of known gender; 27 patients #35 yr old). Findings indicated that most patients with HSTCL who received long-term therapy ($2 yr) with thiopurines for IBD were men, young (#35 yr old), and that no cases of HSTCL were observed in patients treated with anti-TNFs alone. The authors concluded that in young male patients with IBD, a combined treatment with thiopurines and anti-TNFs should be considered only if a clear benefit is expected.84 In 2013, Selvaraj et al85 in a systematic review aimed to identify demographic and clinical characteristics associated with HSTCL in patients with CD and to assess strength of evidence for a causal relationship between medications and HSTCL in CD.85 Overall, 37 cases of HSTCL in CD reported were typically young (,40 yr) and male (86%). The most commonly reported medications were antimetabolites (97%) and anti-TNFs (76%). However, the dose and duration of treatments were not consistently reported, and that conventional treatments were rarely reported. It is therefore concluded that establishing a causative effect other than “possible” between HSTCL and immunomodulators was not feasible, due to incomplete data in case reports and due to the difficult safety assessment in case of rare events, as HSTCL. Minimum reporting requirements for case reports are therefore recommended to improve causality assessment.85

Immunomodulators in IBD Patients with a Positive History of Neoplasia The possible role played by immunomodulators in determining the cancer risk in subgroups of patients with IBD is giving rise to concerns regarding the safety using thiopurines and anti-TNFs in patients with IBD with a history of cancer. The only published studies include studies from the French group, explored in 2013 by Beaugerie et al,86 where the risk of new or recurrent cancer among patients with IBD and previous cancer, exposed or not to immunosuppressants. The analysis included the 17,047 patients of the CESAME prospective

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observational cohort. Among these 17,047 patients, 405 had a diagnosis of cancer previous to study entry.87 Findings suggested that patients with IBD with a history of cancer are at increased risk of developing recurrent or new cancer (21.1/1000 pt-yr and 6.1/1000 ptyr, respectively; HR, 1.9; 95% CI, 1.2–3.0; P ¼ 0.003). New and recurrent cancer rates in patients with previous cancer not treated (n ¼ 312) or treated (n ¼ 93) with immunosuppressants were 13.2/1000 PY and 6.0/1000 PY versus 23.1/1000 PY and 3.9/1000 PY, respectively; (P ¼ NS). Findings supported that patients with IBD with a history of cancer are at increased risk of new or recurrent cancer, with a predominant incidence of new cancers, whereas immunosuppressants seem to have no major impact on this risk.86 In 2013, Beaugerie87 reviewed the few available data regarding the use of immunosuppressants and biologics in patients with previous cancer. The analysis supported that thiopurines may promote EBV-related lymphomas, NMSC, and acute myeloid leukemias, whereas antiTNFs may inhibit or activate carcinogenesis. In the CESAME cohort, patients with previous cancer at entry showed no excess incidence of recurrent or new cancer. It is concluded that the decision to start or resume immunomodulators in patients with IBD with recent cancer should be discussed case-by-case with cancer specialists. However, on the basis of findings from transplant specialists, Beaugerie87 suggested not to consider a waiting period before using immunomodulators for women with adequately treated uterine HG cervical dysplasia. Differently, for invasive cancers, for patients with no aggressive IBD, the authors suggested a waiting period of 2 years using for IBD treatment 5-ASA, steroids, nutritional therapy, or surgery. A longer waiting period of 5 years was suggested for the most aggressive forms of cancers (i.e., melanomas, aggressive breast cancers, sarcomas, urinary tract cancers, and myelomas).87

Immunomodulators and Reduced Risk of Colon Cancer in IBD Evidences from animal models strongly support that chronic inflammation associated with colitis is significantly associated with the development of colitis-associated cancer.2 Moreover, the expression of TNF-alpha has been reported to be associated with CRC in animal models, and the use of TNF-a blockers, including etanercept, has been reported to reduce the number and size of CCR in experimental models.4 The role of ongoing long-term chronic inflammation as observed in colitis, in determining the development of CRC in IBD is also supported by “ex vivo” and “in vivo” findings supporting that 5-ASA may have a role in reducing the frequency of CRC in patients with UC and CD colitis.11 Whether treating patients with IBD with anti-TNFs may reduce the risk of CCR has been postulated on the basis of findings from animal models and observational studies.45,46 In 2013, Beaugerie et al12 evaluated the risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with IBD. As reported in the first paragraph, findings support that although patients with IBD with longstanding extensive UC are at increased risk for CRC, thiopurines may reduce this risk.12 In 2013, Gong et al88 performed a meta-analysis including 9 case-control and 10 cohort studies, to assess the role of thiopurines


for chemoprevention on colorectal neoplasm in IBD.88 Findings from this meta-analysis supported that despite the heterogeneity of the studies considered requires caution, thiopurines had a chemopreventive effect of colorectal neoplasms and a tendency of reducing advanced colorectal neoplasms in IBD. Thiopurines use was indeed associated with a significant decreased incidence of CCR (RR ¼ 0.71; 95% CI, 0.54–0.94; P ¼ 0.017), even after adjustment for duration and extent of IBD. The RR of advanced neoplasm (HG dysplasia and CCR) was 0.72 (95% CI, 0.50–1.03; P ¼ 0.070) and that of cancer was 0.70 (95% CI, 0.46–1.09; P ¼ 0.111) for thiopurine-treated patients.88 In 2013, Rubin et al89 investigated, in a case-control study, the effects of inflammation, therapies, and characteristics of patients with UC on their risk for CR neoplasia (CRN). In univariate analysis, histologic inflammatory activity was positively associated with CRN (OR, 2.56; P ¼ 0.001), whereas immunomodulators (including AZA, 6 MP, and MTX) reduced the risk for CRN (OR, 0.35; P , 0.01). Histologic inflammatory activity was also associated with CRN in multivariate analysis (OR, 3.68; P ¼ 0.001). It is concluded that increased inflammation was associated with CRN in UC and that immunomodulatory use reduced the risk for CRN, suggesting a chemoprotective effects of these drugs. New stratified surveillance and treatment strategies are therefore suggested to prevent and detect CRN in UC.89

SUMMARY The growing knowledge regarding the pathogenesis of IBD is leading to the development of new treatments specifically modulating or targeting the host immune response. Because of the proven efficacy of immunomodulators, including biologic therapies, these treatments are widely used for treating patients with IBD. More recently, these treatments are used not only during severely active phases of IBD but also during earlier phases of the disease and/or in patients showing predictive markers of aggressive disease course. The widespread use of immunomodulators and antiTNFs is however rising concern regarding the possible cancer risk using these treatments in IBD, particularly at young age. IBD already bears an increased risk of lymphoma, particularly NHL in CD, even in patients not treated with immunomodulators or antiTNFs. Consistent evidences support that thiopurines increase the risk of lymphoma in IBD, most often associated with EBV infection. Combined treatment with thiopurines and anti-TNFs has been shown to significantly increase the risk of lymphoma, including the risk of a rare HSTCL. Male gender and young age in patients with CD have been shown to be associated with a significantly higher risk of this often fatal lymphoma. Despite these warnings, the overall risk of lymphoma using thiopurines alone or in combination with anti-TNFs in IBD is low, and all current knowledge supports that, in selected patients, the benefits of using these treatments significantly overwhelm the lymphoma risk. When considering solid tumors, patients with UC and CD colitis, particularly with a long-term history of IBD, may be associated with a slightly increased risk of CRC, although the use


of mesalazine has been suggested to reduce this risk during the last years. As for CRC, the risk of SBC also has been reported to be increased in patients with longstanding small bowel CD, and a protective role for anti-inflammatory drugs, including mesalazine, has also been suggested at this purpose. The long-term use of thiopurines also has been shown to reduce the risk of CRC in UC and CD colitis, most likely because of their efficacy in treating the inflammatory process at the gut level. Accordingly, observations in animal models suggest that anti-TNFs may reduce the risk of colitis-associated colon cancer, thus supporting that this mechanism may be applied also for patients with IBD. Patients with IBD have recently been shown to have also an increased risk of NMSC and melanoma, independent of treatment with immunomodulators. Recent independent observations also support that thiopurines used alone or in combination with anti-TNFs, increase the risk of NMSC, particularly of squamous cell skin cancer. The role played by anti-TNFs in determining the risk of NMSC in IBD has not been clarified. Differently, anti-TNFs have been reported to increase the risk of melanoma, particularly in CD. These observations support the need of sun protection and dermatologic screening and followup for all patients with IBD before and during treatment with thiopurines and/or anti-TNFs. Cervix dysplasia/cancer has also been suggested to be associated with CD, although the possible relationship with immunomodulators is not clarified. More recently, very preliminary findings also support that the frequency of cancers involving the urinary and genitourinary tract may be increased in IBD, although the possible relation with thiopurines and/or antiTNFs use is under investigation. Among limitations of the analysis regarding the risk of cancer using immunomodulators in IBD, there are differences in terms of study design, study population, and dose/duration of treatments. Moreover, whether the development of any cancer may be related to specific treatments for IBD is often difficult due to the multiple concomitant or sequential treatments for the disease most often used in these patients. Studies investigating the cancer risk using immunomodulators in IBD do not also take into account other well-known risk factors of cancer (i.e., smoke, family history), thus not allowing a proper evaluation of the real role played by IBD treatments in the development of cancer. The wide range of follow-up duration among different studies also represents one of the major limitations when investigating the role played by immunomodulators in determining the cancer risk in IBD. Moreover, the use of antiTNFs alone or in combination with thiopurines can be assessed only after the first trial using IFX in CD published in 1995. Therefore, 19 years is the maximum follow-up of IBD (CD) patients treated with anti-TNFs. Because of the limited number of evidences, the cancer risk associated with the use of biologics different from IFX and adalimumab is unknown, as also the risk associated with the use of immunomodulators different from AZA and 6-MP (i.e., methotrexate, calcineurin inhibitors). Additional point is that the cancer risk related or not to immunomodulators in IBD has been extensively investigated when considering the whole group of patients. The severity of the disease and the extent of the lesions have been properly considered only for www.ibdjournal.org |

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CRC in UC and CD colitis. Preliminary observations however may suggest that the severity and extent of IBD (pancolitis in UC, fistulizing CD) may also play a role in the development of extraintestinal cancers. Whether an ongoing severe chronic inflammation may increase the overall risk of cancer is under investigation. This issue may assume relevance as patients with IBD with a more severe and aggressive course are those patients more frequently requiring immunomodulatory drugs, potentially able to increase the risk of specific cancer histotypes. The review of the main studies assessing the cancer risk using immunomodulators in IBD supports that these treatments do not to increase the overall risk of malignancies in patients with UC and CD. Nevertheless, the risk of specific cancers, including lymphoma, HSTCL, and NMSC is increased by using thiopurines, and the combined use of thiopurines and anti-TNFs significantly increases the risk of NMSC, lymphoma, and particularly of HSTCL. These observations derive from current evidences and are in agreement with current guidelines at this regard.1,21,61,90–94 Recent evidences also support that anti-TNFs may increase the melanoma risk. Whether IBD is associated with an increased risk of urinary cancer and the role played by immunomodulators are under investigation. The combined role played by the severity of IBD and the use of immunomodulators needs also further studies aimed to identify the subgroups of patients with IBD at higher risk of developing cancer when using immunomodulators. Current evidences therefore indicate that, in experienced hands, the use of thiopurines and/or anti-TNFs represents a significant achievement in clinical management of patients with IBD. Nevertheless, physicians must be aware that using thiopurines and anti-TNFs may increase the risk of specific cancer histotypes. Indication for immunomodulators should therefore be given by dedicated gastroenterologists in carefully selected compliant patients under regular follow-up.

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Long-term safety of immunomodulators in pediatric inflammatory diseases.

Antibiotics and inflammatory bowel diseases.

Inflammatory mediators in chronic inflammatory bowel diseases.

Inflammatory bowel diseases.

Inflammatory bowel diseases. Preface.

Costs in inflammatory bowel diseases.

Rectal cancer in inflammatory bowel diseases: MR imaging findings.

Genetics of Inflammatory Bowel Diseases.

Serum inflammatory markers and risk of colorectal cancer in patients with inflammatory bowel diseases.

Neurological disorders and inflammatory bowel diseases.

Inflammatory bowel disease and airway diseases.

Familial inflammatory bowel diseases in Northwest Greece.

Management of arthropathy in inflammatory bowel diseases.

Update imaging in inflammatory bowel diseases.

[Lactose intolerance in chronic inflammatory bowel diseases].

Psychological Interventions for Irritable Bowel Syndrome and Inflammatory Bowel Diseases.

Hyperlipasemia in Pediatric Inflammatory Bowel Diseases.

Letter: diverticulosis in inflammatory bowel diseases.

Thiopurine-induced pancreatitis in inflammatory bowel diseases.

Proinflammatory progranulin antibodies in inflammatory bowel diseases.

Neurologic manifestations of inflammatory bowel diseases.

The microbial basis of inflammatory bowel diseases.

Experimental Models of Inflammatory Bowel Diseases.

Selenium and selenoproteins in inflammatory bowel diseases and experimental colitis.