43Why Aren’t All TNFs the Same?
While anti-TNF medications represent an effective class of therapy for CD, not all
anti-TNFs are equal. There is currently no prospective head-to-head trial or two
anti-TNFs; however, some anti-TNFs have their key benefit only in certain sub-
groups (e.g., CZP only met induction end points for the high CRP subgroup), while
others do not appear to work in CD. Etanercept is an anti-TNF commonly used in
RA that failed to demonstrate clinical efficacy for CD in a phase II trial [ 64 ]. Other
anti-TNFs also failed to produce a benefit in phase II and III trials for CD [ 65 – 68 ].
Differing clinical activity between drugs is likely influenced by different in vitro
mechanisms. For example, while IFX can bind both the monomeric (inactive) and
trimeric (active) form of soluble TNF and results in a stable complex [ 69 ], etaner-
cept predominately binds the active form of soluble TNF and does not form as sta-
ble a complex as other anti-TNFs, which can lead to dissociation of the drug and
target [ 70 ]. Etanercept does have the benefit of binding lymphotoxin (TNF-beta),
but that does not appear clinically relevant in CD [ 71 ]. The drug makeup itself may
also play a role in efficacy. Notably, only IgG1 monoclonal antibodies have thus far
demonstrated achievement in all relevant outcomes including clinical remission,
reduction of CRP, and mucosal healing [ 72 ].
There are key administration and dosing differences between the three anti-TNFs
that also likely contribute to varying efficacy and may influence decision-making in
certain clinical scenarios. IFX is the only FDA-approved anti-TNF that is an infu-
sion (IV). The benefits of an infusion are quick time to peak serum drug concentration
and easy ability to vary the dose. ADA and CZP are subcutaneous (SC) injections
that are typically fixed-dose prefilled pens, although syringes are available. The
benefits of an injection are ease of patient use (typically at home) and lower health-
care utilization cost when compared to an infusion center [ 73 ].
Beyond these clinical differences, there are pharmacokinetic differences between
IV and SC routes that are important. IV administration allows for reproducible bio-
availability with each infusion, while the SC route likely involves uptake through
the lymphatic system followed by a slowed release into the vascular system [ 74 ].
This process can result in variable bioavailability and longer time to peak drug con-
centration. Additionally, due to dendritic cells in the skin, the SC route may increase
the probability of developing antidrug antibodies [ 75 ]. Without direct comparison
trials, it is impossible to ubiquitously recommend a single anti-TNF over another.
Rather, the decision to start a specific anti-TNF should incorporate patient factors
(preference, prior therapy, insurance coverage), pharmacokinetic factors (need for
rapid, high drug concentrations, antibody development), and cost.
Conclusion
In summary, the class of anti-TNFs have clearly changed the landscape for treat-
ing CD. They are effective at inducing and maintaining remission, mucosal heal-
ing, and fistula healing. Overall, they appear to be cost-effective due to short-term
3 Antitumor Necrosis Factor Agents in Crohn’s Disease