In the Journals

IBD patients on thiopurines, anti-TNFs show ‘small but significant’ lymphoma risk

Patients with inflammatory bowel disease who used thiopurines or anti-tumor necrosis factor agents showed a “small but statistically significant” increase in their risk for lymphoma, according to new research published in JAMA.

Notably, lymphoma risk was higher when patients used thiopurines and anti-TNFs in combination.

“These findings may inform decisions regarding benefits and risks of treatment,” investigators wrote.

While increased lymphoma risk has been reported among IBD patients treated with thiopurines, it remains unclear whether anti-TNFs, either alone or in combination with thiopurines, carry the same risk. Investigators therefore evaluated data on 189,289 adults with IBD identified within French National Health Insurance databases (median age, 43 years; 54% women; median follow-up, 6.7 years).

Overall, 65% remained unexposed to anti-TNFs and thiopurines throughout follow-up, 27% received thiopurine monotherapy for an average of 17 months, 16% received anti-TNF monotherapy for an average of 19 months, and 7.5% received combination therapy with both thiopurines and anti-TNFs for an average of 8 months between 2009 and 2015.

Investigators noted that when treatment began, 6% of the thiopurine monotherapy group had previously received anti-TNF monotherapy for an average of 8 months, 35% of the anti-TNF monotherapy group had previously received thiopurine monotherapy for an average of 12 months, 50% of the combination therapy group had previously received thiopurine monotherapy for an average of 7.5 months, and 43% of the combination therapy group had previously received anti-TNF monotherapy for an average of 7 months.

In total, 336 patients received a diagnosis of lymphoma, mostly men (57%) with Crohn’s disease (54%) at a median age of 60 years. These cases occurred in:

  • 220 patients in the unexposed group (incidence rate [IR] = 0.26; 95% CI, 0.23-0.29 per 1,000 person-years);
  • 70 in the thiopurine monotherapy group (IR = 0.54; 95% CI, 0.41-0.67);
  • 32 in the anti-TNF monotherapy group (IR = 0.41; 95% CI, 0.27-0.55); and
  • 14 in the combination therapy group (IR = 0.95; 95% CI, 0.45-1.45).

“Hodgkin lymphoma accounted for 14% of all lymphomas among unexposed patients, 19% among patients exposed to thiopurines, 19% among patients exposed to anti-TNF agents, and 43% among patients exposed to combination therapy,” investigators noted.

Multivariable analysis showed an increased lymphoma risk in the thiopurine monotherapy group (adjusted HR [aHR] = 2.6; 95% CI, 1.96-3.44), in the anti-TNF monotherapy group (aHR = 2.41; 95% CI, 1.6-3.64), and in the combination therapy group (aHR = 6.11; 95% CI, 3.46-10.8) compared with the unexposed group (P < .001 for all). Further, while the risk did not differ between monotherapy groups, the combination therapy group showed a higher lymphoma risk compared with the thiopurine monotherapy (aHR = 2.35; 95% CI, 1.31-4.22) and anti-TNF monotherapy groups (aHR = 2.53; 95% CI, 1.35-4.77; P < .001 for both).

The researchers noted these increased risks were observed for both non-Hodgkin lymphoma and Hodgkin lymphoma, and that the results did not differ based on age, sex, IBD type, or anti-TNF agent among those exposed to either Humira (adalimumab, AbbVie) or Remicade (infliximab, Janssen). Additional independent associations with lymphoma risk included increasing age, male sex, Crohn’s disease, and smoking-related conditions.

“Although these differences in the risk of lymphoma were significant in relative terms, their absolute magnitude of less than 1 case per 1,000 person-years should be considered against the potential benefit of successful treatment of IBD,” the researchers concluded. – by Adam Leitenberger

Disclosures: One of the authors (Carrat) reports serving as a consultant for Imaxio, and another (Carbonnel) reports receiving personal fees and/or nonfinancial support from Enterome, Falk, MSD, Medac, Bristol-Myers Squibb, Janssen, Takeda, AbbVie, and FMC HE, and he also serves as a consultant for Genentech, Otsuka, and Vifor and as a reviewer for Hospira.

Patients with inflammatory bowel disease who used thiopurines or anti-tumor necrosis factor agents showed a “small but statistically significant” increase in their risk for lymphoma, according to new research published in JAMA.

Notably, lymphoma risk was higher when patients used thiopurines and anti-TNFs in combination.

“These findings may inform decisions regarding benefits and risks of treatment,” investigators wrote.

While increased lymphoma risk has been reported among IBD patients treated with thiopurines, it remains unclear whether anti-TNFs, either alone or in combination with thiopurines, carry the same risk. Investigators therefore evaluated data on 189,289 adults with IBD identified within French National Health Insurance databases (median age, 43 years; 54% women; median follow-up, 6.7 years).

Overall, 65% remained unexposed to anti-TNFs and thiopurines throughout follow-up, 27% received thiopurine monotherapy for an average of 17 months, 16% received anti-TNF monotherapy for an average of 19 months, and 7.5% received combination therapy with both thiopurines and anti-TNFs for an average of 8 months between 2009 and 2015.

Investigators noted that when treatment began, 6% of the thiopurine monotherapy group had previously received anti-TNF monotherapy for an average of 8 months, 35% of the anti-TNF monotherapy group had previously received thiopurine monotherapy for an average of 12 months, 50% of the combination therapy group had previously received thiopurine monotherapy for an average of 7.5 months, and 43% of the combination therapy group had previously received anti-TNF monotherapy for an average of 7 months.

In total, 336 patients received a diagnosis of lymphoma, mostly men (57%) with Crohn’s disease (54%) at a median age of 60 years. These cases occurred in:

  • 220 patients in the unexposed group (incidence rate [IR] = 0.26; 95% CI, 0.23-0.29 per 1,000 person-years);
  • 70 in the thiopurine monotherapy group (IR = 0.54; 95% CI, 0.41-0.67);
  • 32 in the anti-TNF monotherapy group (IR = 0.41; 95% CI, 0.27-0.55); and
  • 14 in the combination therapy group (IR = 0.95; 95% CI, 0.45-1.45).

“Hodgkin lymphoma accounted for 14% of all lymphomas among unexposed patients, 19% among patients exposed to thiopurines, 19% among patients exposed to anti-TNF agents, and 43% among patients exposed to combination therapy,” investigators noted.

Multivariable analysis showed an increased lymphoma risk in the thiopurine monotherapy group (adjusted HR [aHR] = 2.6; 95% CI, 1.96-3.44), in the anti-TNF monotherapy group (aHR = 2.41; 95% CI, 1.6-3.64), and in the combination therapy group (aHR = 6.11; 95% CI, 3.46-10.8) compared with the unexposed group (P < .001 for all). Further, while the risk did not differ between monotherapy groups, the combination therapy group showed a higher lymphoma risk compared with the thiopurine monotherapy (aHR = 2.35; 95% CI, 1.31-4.22) and anti-TNF monotherapy groups (aHR = 2.53; 95% CI, 1.35-4.77; P < .001 for both).

The researchers noted these increased risks were observed for both non-Hodgkin lymphoma and Hodgkin lymphoma, and that the results did not differ based on age, sex, IBD type, or anti-TNF agent among those exposed to either Humira (adalimumab, AbbVie) or Remicade (infliximab, Janssen). Additional independent associations with lymphoma risk included increasing age, male sex, Crohn’s disease, and smoking-related conditions.

“Although these differences in the risk of lymphoma were significant in relative terms, their absolute magnitude of less than 1 case per 1,000 person-years should be considered against the potential benefit of successful treatment of IBD,” the researchers concluded. – by Adam Leitenberger

Disclosures: One of the authors (Carrat) reports serving as a consultant for Imaxio, and another (Carbonnel) reports receiving personal fees and/or nonfinancial support from Enterome, Falk, MSD, Medac, Bristol-Myers Squibb, Janssen, Takeda, AbbVie, and FMC HE, and he also serves as a consultant for Genentech, Otsuka, and Vifor and as a reviewer for Hospira.

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