Infliximab has proven clinical efficacy in patients with active AS, which is associated with definite improvement of disease activity in both the short and the long term, for up to 3 years [5
]. Our study is the first to examine the clinical response to discontinuation of long-term infliximab therapy in patients with AS. Several important observations were made.
First, we found that discontinuation of long-term therapy with infliximab in patients with AS leads to a clinical relapse of the disease, with deterioration of signs and symptoms, after several weeks to months. This indicates that the majority of patients may, rather, need continuous anti-TNF therapy.
Another finding is that even though there were relapses eventually, in many patients the low disease activity at discontinuation of therapy persisted for some weeks after discontinuation, although only one patient was in ongoing remission for more than 1 year. The mean duration of ongoing response was almost 4 months. Since the time of persistent clinical efficacy of infliximab after discontinuation varied widely between patients, the optimal dose and the optimal infusion interval for infliximab is also likely to be different from patient to patient. The best dosage probably needs to be defined individually.
We also found that there seem to be predictive factors for the duration of clinical improvement after discontinuation of infliximab therapy in AS patients. The data suggest that clinical improvement persists longer when a state of partial remission, low disease activity, and low CRP levels are present at the time of discontinuation. Thus, the outcome after discontinuation can be partly predicted.
These conclusions are complementary to those predictive of major response that have been reported recently [15
]. Overall, it seems that patients who may be candidates for discontinuation or a possible extension of infusion intervals of infliximab therapy have a better outcome if this decision is made while the patients are in a state of low disease activity. Such patients are more likely to have ongoing benefit from previous therapy for several more months.
The favorable response after retreatment argues against an important role of formation of antibodies to infliximab (ATI) in these patients. This response is probably due to the preselection of the patients by the previous 3 years of persistent high-dose therapy with infliximab, which clearly differs from other approaches [16
Discontinuation of infliximab may become necessary in various patients: those who are in remission for long periods and simply want to test the remission; those who want to become pregnant and wish to exclude the risk of medication toxicity (although there is no indication that infliximab may be harmful); those with more severe or repetitive infection(s); and those who have to undergo surgery (although there is no reason to think that ongoing infliximab therapy may be harmful, good data are lacking).
Another finding of our study is that discontinuation of infliximab therapy seems justified, since we found that retreatment with infliximab was safe, resulting in a good clinical response, similar to that before discontinuation. There was no loss of efficacy and no need for an increased dose after the new start of infliximab therapy. Thus, if for any reason discontinuation of anti-TNF therapy is considered necessary, that seems possible with no major problems regarding efficacy and safety. This may have definite implications for daily practice, since discontinuation of therapy at certain intervals, such as after 1 or 2 years of therapy, may become a standard approach. Payers and patients may want to make sure that further anti-TNF therapy is needed. An intermittent cessation of anti-TNF therapy may be considered in the case of patients who respond well to infliximab therapy for longer periods of time. Since it is unknown how long the patients should receive anti-TNF therapy, it is unclear how to deal with this uncertainty in clinical practice. One possible approach would be to check from time to time whether the disease is still active or has become active again after initial improvement due to infliximab therapy. Another possibility would be to slowly extend the intervals between infusions. This approach would obviously have important economic implications.
However, we think that no clear recommendation for such an approach can be given in the light of present knowledge. More work is needed to confirm our findings and further studies are required to better clarify these issues.
The decision to use a BASDAI cutoff score of 4 is based on the ASAS recommendations. The decision to use a cutoff score of 3 to indicate low disease activity is, at the moment, arbitrary but may serve as a basis for further discussion. It will be especially interesting to learn from the patients whether a score of 3 comes closer to indicating an acceptable state.