5 common problems with anti-TNF drugs in IBD and 5 potential solutions to implement now
Anti-TNF drugs are highly effective and widely available for patients with IBD.
We use infliximab - often in combination with azathioprine - for our sickest patients: acute severe colitis; fistulising Crohn's disease. The evidence base for inducing and maintaining remission, mucosal healing, fistula healing is robust. The safety profile is well established. Multiple biosimilar infliximab and adalimumab molecules are now available at a fraction of the cost of the originators. We have massively expanded anti-TNF therapy as a result.
Early effective therapy based on anti-TNF drugs is a game-changer in IBD.
However, we have a number of problems with anti-TNF drugs
about 30% of patients will not respond (primary non-response - PNR)
a further 20% will lose response in year one alone (secondary loss of response)
immunogenicity rates rates are high and drive loss of response
safety issues remain a concern, especially for certain patient groups
when anti-TNF drugs fail, other drugs work less well (our drug sequencing problem)
Here are five potential solutions
1. Think about immunogenicity early, because it often starts early
What is your strategy? If using infliximab, it should nearly always be combination therapy - start the immunomodulator early - aim for AZA dose ~1.5mg/kg for at least 6m.
Monotherapy often a good starting point for ADA; but act quickly if early signs of immunogenicity. If using ADA after IFX immunogenicity then always start with combo.
2. Dose optimise early
We lack controlled trial data to support proactive TDM. The SERENE studies did not support higher induction regimens with ADA However, low drug levels at week 14 in PANTs were associated with PNR, as well as immunogenicity and lower response at one year. High CRP, low albumin, obesity all associated with low drug levels.
I hae a low threshold to dose optimise - it is cost effective, with no safety concerns.
3. Use subcutaneous infliximab
The currently available data point to a) subcut IFX is as effectie as intravenous IFX; b) is as well tolerated; c) has a better pharmacokinetic profile; and d) subcut MAY be ok as monotherapy for some. We need more data to support this.
Subcut IFX is currently more expensive than IV IFX. But our initial experience is promising.
4. Avoid drug holidays and drug stopping without good reason
Longer than planned gaps between doses of anti-TNF drug - especially those of >6m -increases the risk of immunogenicity. In Crohn's disease, I usually keep anti-TNF going.
5. Use another class of drug
It may be more appropriate to start with a non-anti-TNF based strategy, including:
where anti-TNF is contra-indicated and/or where combination therapy is ruled out
in bionaive Crohn's disease SEAVUE showed us that USTE = ADA
where there is evidence of superiority (e.g. VEDO>ADA in UC from VARSITY)
guided by HLA-DQA1*05 status - looking forward to new data to inform this approach
New therapies are on the way that offer the same / better effectiveness than anti-TNF, with excellent persistence (low immunogenicity) and low risk safety profiles. These will make excellent first-line options, but initially they will be more expensive.
Importantly, they should work better than current options when anti-TNF drugs fail.