Risk of Lymphoma Associated with Anti-TNF Therapy in Patients with Inflammatory Bowel Disease: Implications for Therapy

Figures & data

Table 1 Summary of Studies and Reviews Addressing Lymphoma Risk with ATA Monotherapy Since January 2013

Author	Publication Year	Country	Study Design	Median Observation Period	Diagnosis	Cases of Lymphoma	Main Results	Increased Risk of Lymphoma with ATA Monotherapy?
Afif, et al^Citation12	2013	US	Nested case-control	-	80 IBD w lymphoma, 160 matched IBD controls	9 ATA, 71 unexposed	OR: 2.04 (95% CI 0.32–12.79)	No
Haynes, et al^Citation21	2013	US	Retrospective cohort	1508 PYF	6357 IBD; 2657 ATA (96.8% IFX, 3.2% ADA), 3700 TP	<5 cases ATA, ~6 cases TP	HR 0.41 (95% CI, 0.07–2.35)	No
Deepak, et al^Citation16	2013	US	Case-control	-	91 cases T-cell NHL (36 CD, 9 UC, 46 other autoimmune diseases)	7 cases ATA mono (1 case HSTCL in CD patient), 38 cases ATA + IMM (24 cases HSTCL)	Risk T-cell NHL in all conditions: ATA +TP (95% CI 4.98–354.09, p<0.0001); TP mono (95% CI 8.32–945.38; p<0.0001), ATA mono (95% CI 0.13–10.61; p=1.00)	No
Williams et al^Citation25	2014	UK	Pooled analysis: 22 RCTs (11 IFX, 6 ADA, 4 CZP, and 1 GLM)	Maximum 56 weeks	7054 IBD (4566 CD and 2488 UC)	0 in treatment arm, 3 in placebo arm	RR malignancy 0.77 (95% CI 0.40–2.02)	No
Osterman, et al^Citation26	2014	US	Post hoc analysis	1.61 yrs	1594 CD patients (900 ADA mono, 694 ADA + IMM, 563 ADA + TP only)	2 (1 ADA + TP, 1 ADA + MTX, 0 ADA mono)	ADA + TP: SIR 8.03 (95% CI 0.97–29.0)	No
Lichtenstein, et al^Citation27	2014	US	Prospective cohort	5.2 yrs	6273 CD (3420 IFX, 2509 other treatment)	14 (8 IFX, 6 other treatment, IMM history in 10 cases)	HR 0.98 (95% CI 0.34–2.82)	No
Nyboe Andersen, et al^Citation23	2014	Denmark	Prospective cohort	3.7 yrs	56,146 with IBD; 4553 ATA exposed, 51,593 ATA unexposed	6 exposed to ATA, 260 unexposed to ATA	RR decreased from 1.36 (95% CI, 0.67–2.76) to 0.90 (95% CI, 0.42–1.91) when adjusted for TP exposure	No
Beigel, et al^Citation22	2014	Germany	Retrospective cohort	4 yrs	666 IBD patients	5 (4 in TP exposed, and 1 in ATA group w previous TP exposure)	HR malignancies 4.15; 95% CI 1.82–9.44; p=0.0007	No
Kopylov, et al^Citation13	2015	Canada	Nested case-control study	-	19,852 IBD (121 cases NHL, 1201 IBD control)	121 cases of NHL (92 no use TP/ATA, 26 TP mono, 0 ATA mono, 3 combo)	ATA mono: RR 0 TP mono: RR 0.87 (95% CI 0.53–1.41) Combo: RR 3.10 (95% CI 0.72–13.48)	No
Biancone et al^Citation20	2016	Italy	Nested case-control study	-	44,619 IBD (21,953 CD and 22,666 UC)	6 CD patients (1 TP monotherapy, 2 combo, 0 ATA mono, 3 no ATA or TP)	OR combo therapy: 2.15 (1.16–4.10); OR ATA therapy: NA as no cases	Unable to assess as no cases in ATA mono
D’Haens et al^Citation24	2017	Multinational	Prospective cohort	60.4 mos for IFX group	1541 CD on IFX, 1121 CD on CT	9 in IFX group, 0 in conventional treatment group. 5/9 patients were on TP as well as IFX	HR = 1.44; 95% CI: 0.86, 2.42, p= 0.163 for lymphoproliferative disorder/malignancy risk	No
Lemaitre, et al^Citation14	2017	France	Retrospective cohort	6.7 yrs	189,289 IBD	336 (220 unexposed, 70 TP mono, 32 ATA mono, 14 ATA/TP combo)	ATA: IR, 0.41; 95% CI 0.27–0.55; aHR, 2.41; 95% CI, 1.60–3.64 Combo: IR, 0.95; 95% CI, 0.45-0.145; aHR, 6.11; 95% CI, 3.46–10.8	Yes
D’Haens et al^Citation15	2018	Multinational	Prospective cohort	~ 3 yrs	5061 CD on ADA	10 (9/10 cases reported prior or current TP use)	Observed rate (0.06 E/100 PYs) lower than estimated background rate (0.084 E/100 PYs)	Not higher than expected
Yang, et al^Citation17	2018	China	Meta-analysis: 2 RCTs, 10 cohort	Maximum 11 yrs	285,811	80 cases in 57,581 exposed to ATA, 790 cases in 284,449 unexposed to ATA	ATA exposed versus unexposed: IRR 1.43 (95% CI 0.91–2.25), RR 0.83 (95% CI 0.47–1.48) Combo versus unexposed: IRR 3.36 (95% CI 2.23–5.05), RR 1.90 (95% CI 0.66–5.44)	No
Bernardes, et al^Citation18	2018	Portugal	Case series	-	900 IBD	6 cases (5 CD, 1 UC)	1 case ATA only, 1 ATA w TP exposure, 4 no ATA or IMM exposure	-
Kobayashi, et al^Citation28	2020	Japan	Retrospective cohort	30.8 mos (mean)	75,673 IBD (6062 ATA only, 7042 TP only, 5754 combo)	103 cases NHL	ATA mono: IRR 0.99, p = 0.455 TP mono: IRR 0.96, p = 0.518 Combo: IRR 1.18, p = 0.094	No

Abbreviations: ATA, anti-tumor necrosis factor alpha; RA, rheumatoid arthritis; HSTCL, hepatosplenic T-cell Lymphoma; PYF, person years follow-up; Mono, monotherapy; IMM, immunomodulator therapy; CT, conventional therapy; TP, thiopurine; IFX, infliximab; ADA, adalimumab; IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; NHL, non-Hodgkin’s lymphoma; CZP, certolizumab; GLM, golimumab; CI, confidence interval; IRR, incident rate ratio; RR, relative risk; OR, odds ratio; aHR, adjusted hazard ratio; NA, not applicable; MTX, methotrexate; Combo, combination therapy; AGA, American Gastroenterological Association.

Afif W, Sandborn WJ, Faubion WA, et al. Risk factors for lymphoma in patients with inflammatory bowel disease: a case-control study. Inflamm Bowel Dis. 2013;19(7):1384–1389. doi:10.1097/MIB.0b013e318281325e

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Beigel F, Steinborn A, Schnitzler F, et al. Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti-TNF alpha antibodies. Pharmacoepidemiol Drug Saf. 2014;23(7):735–744. doi:10.1002/pds.3621

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Biancone L, Armuzzi A, Scribano ML, et al. Inflammatory Bowel Disease Phenotype as Risk Factor for Cancer in a Prospective Multicentre Nested Case-Control IG-IBD Study. J Crohns Colitis. 2016;10(8):913–924. doi:10.1093/ecco-jcc/jjw048

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Lemaitre M, Kirchgesner J, Rudnichi A, et al. Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease. JAMA. 2017;318(17):1679–1686. doi:10.1001/jama.2017.16071

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D’Haens G, Reinisch W, Panaccione R, et al. Lymphoma Risk and Overall Safety Profile of Adalimumab in Patients With Crohn’s Disease With up to 6 Years of Follow-Up in the Pyramid Registry. Am J Gastroenterol. 2018;113(6):872–882. doi:10.1038/s41395-018-0098-4

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Yang C, Huang J, Huang X, et al. Risk of Lymphoma in Patients With Inflammatory Bowel Disease Treated With Anti-tumour Necrosis Factor Alpha Agents: A Systematic Review and Meta-analysis. J Crohns Colitis. 2018;12(9):1042–1052. doi:10.1093/ecco-jcc/jjy065

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