105the elderly (≥65 years) and those on chronic narcotics [ 6 , 28 , 30 , 31 ]. The exact
mechanism through which narcotics increase the risk for serious infections and mor-
tality is unclear, and this may simply serve as a proxy for more complicated disease,
disease-related complications, or disease severity, the latter also being indepen-
dently associated with an increased risk for infectious complications [ 28 , 32 – 35 ].
Two important opportunistic infections that should be specifically considered
when starting a concomitant immunosuppressive agent are hepatitis B and Clostridium
difficile (C. diff). The use of immunosuppressive medications increases the risk for
hepatitis B reactivation, with the greatest risk being seen in patients who are hepatitis
B DNA and/or surface antigen positive being treated with long-term combination
therapy with TNF-antagonists [ 36 – 38 ]. The occurrence of C. diff in IBD is associated
with higher morbidity and mortality as compared to the general population [ 39 , 40 ],
and the use of immunosuppressive therapy, but not biologics (TNF-antagonists), has
been associated with an increased risk of developing C. diff [ 36 ].
Malignancy
One of the most important considerations to be made when using concomitant immu-
nosuppressive therapy in IBD is the potential increased risk for developing malig-
nancy [ 41 ]. IBD patients are at an increased risk for malignancy at baseline [ 42 – 45 ],
and the use of TNF-antagonists does not appear to increase this risk overall [ 46 ]. The
concomitant use of immunosuppressive therapy, however, is clearly linked to an
increased risk for malignancy and, in particular, an increased risk for lymphoma
[ 47 – 49 ]. This increased risk for lymphoma is seen with concomitant thiopurine use,
and the two populations at greatest risk for lymphoma development are the elderly
(≥65 years) and young (≤35 years) males who are at a particular increased risk for
the development of a fatal lymphoma subtype, hepatosplenic T-cell lymphoma
(HSTCL). In both subgroups, the risk of lymphoma is duration dependent, with the
greatest risk being seen after 2 years of use [ 49 – 54 ]. Another important malignancy
linked to thiopurine use is skin cancer. Several studies have now demonstrated that
thiopurines increase the risk for nonmelanoma skin cancer (NMSC) development,
and this increased risk is nearly doubled when used in combination with a TNF-
antagonist [ 48 , 55 , 56 ]. The risk of melanoma, however, appears to be increased by
the use of TNF-antagonists but not immunosuppressive agents, and this risk is poten-
tially higher among patients receiving long-term TNF-antagonist therapy [ 56 ].
Opportunities to Optimize the Use of Concomitant
Immunosuppressive Therapy
When combining safety and efficacy data for the use of concomitant immunosuppres-
sive therapy, several opportunities arise to optimize the personalization of these treat-
ment decisions. (Fig. 7.1) Based on prior RAND appropriateness panels, systematic
reviews, and our review of the literature, the use of concomitant immunosuppressive
7 Concomitant Use of Immunosuppressive Therapy with Tumor Necrosis Factor (TNF)