In a previous study, we have shown that ATI formation is frequent when the drug is given episodically, and that concomitant IS reduces immunogenicity and is associated with a longer duration of response.8
In the present study, we show that MTX and AZA are both equally efficacious in preventing infusion reactions and ATI formation, and this effect is seen irrespective of the duration of exposure to immunosuppressant. Both IS improve the pharmacokinetic profile of IFX.
The efficacy data of IFX treatment in rheumatoid arthritis (RA) and Crohn's disease clearly show the synergistic effect of concomitant IS treatment on IFX response.11,12,13,14,15,16
There are several hypotheses on why concomitant IS treatment may lead to better efficacy of IFX. A first explanation is that IS reduce the risk of ATI formation as already shown in the past1,7
and as is also clear from the present study. Our study shows that the prevention of immunogenicity by IS may account for a better short‐term effect of IFX. A second reason may be that AZA and MTX are additive to IFX in inducing apoptosis of lamina propria T lymphocytes and monocytes. Induction of apoptosis has been shown to be one of the main mechanisms of action of IFX and adalimumab.17,18,19,20
Recent data suggest that AZA and MTX are also capable of inducing apoptosis, which could lead to a synergistic effect with IFX. In vitro experiments in peripheral blood mononuclear cells (PBMCs) showed that combination therapy with IFX and IS was associated with an increased induction of PBMC apoptosis and also better suppression of stimulated PBMC proliferation as compared with monotherapy.21
A third mechanism might involve interaction between both drugs. Studies in patients with RA showed that MTX reduces the clearance of IFX, pointing towards an interaction between both drugs.11,22
This interaction has also been shown for IFX and AZA in patients with Crohn's disease. Roblin et al23
observed a significant increase in 6‐thioguanine nucleotide levels within 1–3 weeks after first IFX infusion (p<0.001), without a change in thiopurine S‐methyltransferase enzyme activity. In their study, an increase in 6‐thioguanine nucleotide of >400 pmol/8×108
erythrocytes was strongly related to a favourable response to IFX, with a predictive value of 100%.
There are very few studies that directly compared the efficacy of AZA and MTX. A double‐blind randomised study by Jeurissen et al24
compared AZA and MTX in patients with RA in whom parenteral gold and/or d
‐penicillamine treatment had been unsuccessful. Patients were randomly assigned to AZA (100 mg daily; n
33) or oral MTX (7.5 mg weekly; n
31) and were followed up for 48 weeks. At 6 months, significantly more improvement was noted in the MTX group in terms of swollen joints, pain, erythrocyte sedimentation rate, C‐reactive protein level and disease activity score, and overall results showed that MTX was superior to AZA in the treatment of RA. Nevertheless, the situation may be different in Crohn's disease where oral MTX has not proven efficacious.25,26
A reason for this is that the absorption of MTX is highly variable and, when compared with oral dosing, intramuscular administration gives more consistent blood levels. However, no randomised studies that have directly compared AZA with MTX in Crohn's disease are available.
The present study again shows that episodic treatment with IFX is not a good strategy in Crohn's disease. When it comes to immunogenicity, it is clear from the large randomised controlled trials and cohort studies that maintenance treatment is preferred over episodic treatment to reduces the risk of antibody formation. Also, the concomitant use of IS and pretreatment with steroids reduces the risk of ATIs and of infusion reactions. Which of these strategies will optimally protect the patient is, however, unclear. In the ACCENT I Study, the lowest incidence of infusion reactions occurred among patients receiving both steroids and IS (8%) compared with patients receiving only IS (20%) or only steroids (23%).1
Our data show that even episodic dosing with concomitant IS therapy still leads to antibody formation in 46% of patients. These patients are very likely to lose clinical response. Maintenance treatment is also superior to episodic treatment for other reasons. The most important advantages of systematic treatment over episodic treatment include better response and remission rates, more thorough mucosal healing, better quality of life and reduced number of disease‐related surgeries and hospitalisations.5,6,7
These effects are probably the consequence of sustained serum IFX levels. In the ACCENT I Study, the difference between scheduled dosing and episodic dosing did not reach statistical significance on all clinical end points; however, follow‐up was relatively short (54 weeks) and the design of the study allowed for dose escalation in the case of loss of response. In fact, almost half of the patients in the episodic dosing group (92/188) had crossed over to the active treatment by week 54.
A striking observation in the present study was the fact that patients who developed ATIs during follow‐up already showed lower IFX levels 4 weeks after the first infusion compared with patients who never developed ATIs. Moreover, an IFX level of <4 μg/ml measured 4 weeks after the first infusion had a PPV of 81% to detect the development of high ATIs during the later course of treatment, and an IFX level of >15 μg/ml measured 4 weeks after the first infusion was 80% predictive for the absence of ATIs during later follow‐up. Therefore, IFX levels measured early after the first infusion of IFX (at 4 weeks) are a good prognostic parameter for development of immunogenicity.
It is at present not known for how long IS with AZA or MTX in combination with IFX should be continued. If IFX is used as a bridge to AZA, a three‐dose induction regimen with infusions given at weeks 0, 2 and 6 should be sufficient, whereafter AZA can be continued alone. However, the recent results of the French GETAID (Group Of Therapeutic Research On The Disease Of Crohn And The Hemorrhagic Rectocolite) were somewhat disappointing in supporting this strategy because the patients who received IFX induction continued to perform better even at 6 and 12 months after starting AZA.27
A different scenario is the one where IFX is administered on an 8‐weekly basis and it is not clear how long concomitant IS therapy should be continued in these patients.
In conclusion, in this study we have shown that concomitant IS treatment reduces the immunogenicity of IFX treatment and is associated with higher IFX levels. We also show that there is no difference between MTX and AZA at reducing the risk for development of antibodies. A striking finding of this study is that the formation of antibodies occurs very early and readily influences the pharmacokinetics of the first IFX dose.