Table 5. Malignancy, data from incidence and observational studies.
| No. of patients (TNF/ Comparator) |
Baseline disease characteristics |
Definition of malignancy |
At Risk Period |
Duration of follow up |
Biologic Arm | Comparator Arm | Reported Incidence | Difference b/n anti-TNF agents |
|
|---|---|---|---|---|---|---|---|---|---|
| Incidence studies | |||||||||
|
| |||||||||
|
DREAM
Kievit et al 2011 [2] |
RA, 1560 |
Duration: 5.5 6 .2 y rs HAQ: 1.3-1.4 DAS 5.0-5.2 |
Patient reported | Not defined |
5 yrs | Etanercept Infliximab Adalimumab |
None | Incidence 0.6/100 pt yrs |
Not studied |
| Flendrie 2003 [3] | RA, 230 | Duration: 11.6 yrs DAS: 6.1 |
NA | 12 months from start of therapy |
NA | Etanercept Infliximab Adalimumab |
None | 2 cases of malignancy reported |
NA |
|
| |||||||||
|
Observational
studies |
|||||||||
|
| |||||||||
| ARTIS Askling 2005 [45] |
TNF/ Inpatient register/ Early RA 4160/ 53067/ 3703 |
HAQ: 1.4 vs. NA vs. 0.7 DAS: 5.6 vs. NA vs. 3.5 |
Swedish Cancer registry, solid cancers |
Ever received TNF |
Mean: 2.3 yrs, 5.6 yrs, 3.6 yrs respectively |
Etanercept, Infliximab, Adalimumab |
Non biologic DMARDs |
Vs. gen population: TNF gp: SIR (CI) 0.9 (0.7-1.2) Inpatient RA: 1.05 (1.01-1.08) Early RA: 1.1 (0.9- 1.3 |
|
| Pay 2008 [46] | Rheumatic diseases 2199 patients on anti-TNF agents |
NA | Reported cases of malignancy in a survey of Turkish patients |
Ever received TNF |
Not applicable |
Etanercept, Infliximab, Adalimumab |
General population, malignancy rates determined by a survey |
l3) 15 malignancy cases SIR (CI) 1.26 (0.7-2.08) |
SIR (CI) Etanercept 2.3 (1.1-4.23) |
| BSRBR Dixon 2010 [47] |
RA TNF, 10735 DMARD, 3235 |
Duration: 11 yrs vs. 9 yrs HAQ:2.2 (0.5) vs. 1.6 (0.7) DAS: 6.7 (1.2) vs. 5.0 (1.3) |
CIS and non- melanoma skin cancers were excluded. Prior malignancy: identified through linkage to UK cancer registers. Incident malignancies were validated and categorized as definite, probable or possible |
After 1st dose of TNF agent or after the registration date for DMARD cohort |
Median: 3.1 person- yrs in TNF cohort vs. 1.9 person -yrs in DMARD cohort |
Etanercept, Infliximab, Adalimumab |
Non biologic DMARDs |
IRR (CI) for incident malignancy: 0.58 (0.23-1.43) Stratifying by time since prior malignancy did not reveal any significant differences in the risk of incident malignancya |
NA |
| RATIO Mariette 2010 [48] |
Rheumatic diseases 57711 patient yrs of anti-TNF treatment compared w/ general French population. |
In lymphoma cases: Duration: 11.0 yrs |
New cases of lymphoma alerted to pharmacovigilance centers or drug companies. In 36/38 cases with biopsies. All cases validated by committee of 3 lymphoma experts. |
Ever received TNF |
2 yrs | Etanercept, Infliximab, Adalimumab |
General French population |
38 lymphoma cases Incidence Rate: 42.1/100 000 pt yrs SIR (CI) 2.4 (1.7-3.2) w/ French population as referent |
SIR Etanercept: 0.9 (p=0.72) Adalimumab: 4.1 (p<0.001) Infliximab: 3.6 p<0.001) Case control arm: OR (CI) Adalimumab vs. Etanercept: 4.7 (1.3-17.7) Infliximab vs. Etanercept 4.1 (1.4-12.5) |
| ARTIS Askling 2009 [49] |
RA 6604 patients in anti-TNF gp, 67743 national RA cohort, 471024 Gen population |
TNF cohort Duration: 10.6 yrs HAQ: 1.4 (0.6) DAS: 5.5 (1.3) |
Cases of lymphoma identified through Swedish Cancer Register (reporting mandatory by treating physician and pathologist) |
Ever received TNF |
9 yrs | Etanercept, Infliximab, Adalimumab |
-Non-biologic DMARDs. -General population |
26 lymphoma cases RR (CI) -TNF gp vs. Non biologic DMARDgp 1.35 (0.82-2.11) - vs. general population 2.72 (1.82-4.08) |
No |
| ARTIS Askling 2005 [50] |
RA 4160 patients in anti-TNF gp Inpatient RA cohort: 53067 Early RA cohort 3703 |
HAQ: 1.4 vs. NAvs. 0.7 DAS: 5.6 vs. NAvs. 3.5 |
Cases of lymphoma identified through Swedish Cancer Register (pathology slides reviewed by investigators) |
Ever received TNF |
4 yrs | Etanercept, Infliximab, Adalimumab |
-Inpatient RA register -Early RA cohort |
TNF cohort vs. Inpatient register cohort RR, 1.1 (CI, 0.6-2.1) Early RA cohort vs. Inpatient register cohort RR, 0.8 (CI, 0.4-1.4) TNF cohort vs. general population SIR, 2.9 (CI, 1.3- 5.5 |
|
| NDB Wolfe 2004 [51] |
RA Anti TNF: 9162 MTX 5593 No MTX, no biologic 4474 |
Duration: 13.7 yrs vs. 13.5 yrs vs. 13.5 yrs HAQ 1.2 (0.7) vs. 1.1 (0 .7) vs. 1.0 (0.7) |
Lymphoma: patient self-report followed by validation by contacting physician or medical records where possible. Based on level of evidence: classified as validated, refuted or likely lymphoma |
Ever received TNF |
2.5 yrs | Etanercept, infliximab | -MTX - No MTX, No biologic |
29 lymphoma cases no Compared to general population SIR (95% CI) All RA: 1.9 (1.3-2.7) TNF gp 2.9 (1.7- 4.9) MTX 1.7 (0.9-3.2) RA, no MTX, no anti-TNF: 1.0 (0.4- 2.5) |
No |
| NDB Wolfe 2007 [52]b |
19591 RA patients total; 10815 patients in anti TNF gp |
All participants: Duration: 14.1 yrs HAQ: Mean 1.1 (0.7) |
Lymphoma reported in patient questionnaires, validated by medical records |
Ever received TNF |
Mean 3.7 yrs |
-Etanercept, Infliximab, Adalimumab -Anti-TNF+ MTX |
-Non anti-TNF DMARDs - - MTX alone |
Anti-TNF vs. non anti-TNF gp OR 1.0 (0.6-1.8) Anti-TNF + MTX vs. MTX alone gp OR 1.1 (0.6-2.0) |
|
| LORHEN Pallavicini 2010 [53] |
1064 RA patients treated w/ anti TNF agents |
Duration (n): < 5yrs=324 5-10 yrs 338 > 10 yrs 402 HAQ: 1.46 DAS: 5.90 |
NA | Ever received TNF |
2 3 months |
Etanercept, Infliximab, Adalimumab |
General population data from Varese and Milan cancer report |
SIR (CI) Overall cancer: 0.94 (0.55-1.48) Solid cancers 0.72 (0.38-1.24) Hematologic cancers 4.08 (1.32- 9.53) Lymphomas 5.99 (1.61-15.35) |
|
| SSATG Geborek 2005 [54] |
RA 757/ 800 |
Duration: 12 yrs vs. 11 yrs HAQ Quartile > 3: 61% vs. 41% |
Swedish cancer registry. All tumors, lymphomas |
Ever received TNF |
Person years: TNF gp: 1603 Comparator gp: 3948 |
Etanercept Infliximab |
Non biologic DMARDs |
TNF group, 5 cases of lymphoma Comparator group, 2 lymphoma cases SIR (95% CI) Vs. general population -Total tumor risk: TNF gp 1.1 (0.6- 1.8) Comparison gp 1.4 (0.6-1.8) -Lymphoma risk: TNF gp 11.5 (3.7- 26.9) -Comparison gp 1.3 (0.2-4.5) |
|
|
| |||||||||
| Pharmacovigilance reports | |||||||||
|
| |||||||||
| Theophile 2011 [55] | Rheumatic diseases 81/61 |
NA | Lymphoma confirmed by histopathological analysis |
Ever on TNF |
NA | Published case reports of lymphoma after Anti-TNF therapy |
Cases of lymphoma after anti-TNF therapy reported to French pharmacovigilance system |
In published case reports, pts were younger (p=0.03), more frequently on 1st TNF (p=0.03), and Crohn’s disease was the main indication of anti-TNF use ( p,0.0001) and in particular involved HSTCL. In pharmacovigilance reports, a succession of anti- TNFs (p=0.03) and adalimumab ( p< 0.0001) were more frequently reported ; RA was the main indication for anti- TNF use. |
|
| Meyboom 2008 [56] | Rheumatic diseases 121 |
NA | Leukemia cases reported to WHO pharmacovigilance program |
Ever on anti-TNF agent |
NA | Leukemia cases in patients on TNF blockers |
None | 121 cases of leukemia reported |
|
a
Subtypes of prior malignancies was balanced in the 2 cohorts, 80% being solid tumors. Prior malignancy: Rate: 1.6% in anti-TNF cohort vs. 3.6% in DMARD cohort
b
incidence rate in NDB cohort overall: 105.9/100000 yrs of exposure. SIR (CI) in NDB cohort vs. SEER 1.8 (1.5-2.2)