Trouble with the tolerability of conventional immunomodulators results in relatively high discontinuation rates despite their ongoing utility in the biologic era, Australian research shows.
A retrospective study of 782 IBD patients on immunomodulators at two tertiary hospitals in Victoria has found discontinuation of methotrexate (40%) occurred at twice the rate as that of dose-optimised thiopurines (19%).
Nausea (15%), fatigue (8%) and hepatotoxicity (7%) were the most common reasons for methotrexate discontinuation. Nausea (3.0%), hepatotoxicity (2.6%), fatigue (2.4%) and arthralgia (2.4%) were the most common reasons for cessation of thiopurines.
The study also found discontinuation rates were higher with subcutaneous methotrexate (45%) than oral methotrexate (32%).
Serious adverse outcomes such as infections, malignancy, ED presentations or hospitalisations were similar in patients on thiopurines or methotrexate.
Withdrawal from thiopurines occurred earlier than from methotrexate (5 v 7 months).
For patients who were able to tolerate therapy for at least six months, there was a trend favouring thiopurines but no significant difference between the rates of long-term endoscopic remission (39% v 24%).
“The relatively poor tolerability of immunomodulator therapy remains a major barrier to their long-term utility in IBD,” the study said.
“This is the largest study to date attempting to further examine this issue in a cohort where modern optimisation of immunomodulator therapy was routinely used.”
Lead author Dr Abhinav Vasudevan, from the department of gastroenterology and hepatology at Box Hill Hospital, told the limbic their centre had a tendency to use thiopurines over methotrexate.
“I think the big difficulty with thiopurines from a patient perspective is that you get all the bad side effects prior to getting the good effects. So most of the side effects as we demonstrate in our study will occur within the first month … [but patients] wouldn’t have developed the good effects as it takes up to three months to reach full efficacy.”
However if patients could get past the early muscle aches, flu-like symptoms and nausea in the first month, most seem to be able to persist with thiopurines long term, he said.
In contrast, he said patients on methotrexate don’t have the initial spike of adverse events in the first 30 days but were more likely to feel nauseous as they keep going with the drug.
“While it doesn’t spike at the start, it seems to continuously get more frequent as time goes on. And that can become quite bad. Some people will even develop anticipatory nausea – so they feel sick even thinking about giving themselves the injection or taking the tablet.”
Dr Vasudevan said there was probably a move towards methotrexate because of concerns with the long term safety with thiopurines.
“So there has been increased publicity of the risk of lymphoma and non-melanoma skin cancers. But if you had to pick one of the two it seems that thiopurines seem to have lower discontinuation rates.”
“When considering which immunomodulator to use, particularly when you are picking something for long term therapy, then I think we would still be advocating for thiopurine therapy as first line over methotrexate unless there is a clear contraindication to that.”