In this study, we evaluated a predefined, infliximab dosing regimen in which patients were eligible to receive dose increases if they did not respond to treatment or if they initially responded but later flared in a double‐blinded fashion. The predefined criteria for dose escalation were used to ensure uniformity in the administration of dose escalations according to changes in the total TJC and SJC. About two‐thirds of patients did not require any dose escalation and continued to receive 3 mg/kg infliximab throughout the 1‐year study. Of the patients who did require dose escalation(s), nearly 80% achieved or regained response using the criteria based on 20% improvement in the TJC and SJC. These data, however, should be viewed with caution as not all patients who met the criteria for response in this study may have had clinically meaningful improvement.
The decision to increase the dose was made beginning at week 22. However, the proportion of patients with an ACR 20 response at week 22 was not substantially higher than that at week 14, suggesting that patients could be evaluated for dose escalation as early as 3 to 4 months. Primary and secondary non‐responders had similar response rates after dose escalation (77% vs 83% response, respectively); thus, both categories of patients responded well to dose escalation. There were no distinguishing baseline clinical characteristics for the patients who required dose escalation.
The results of a previous study of infliximab and MTX in patients with RA indicate that infliximab trough serum concentrations of
1.0 μg/ml are needed to maximise the potential for response.13
In our study, low (<1.0 μg/ml) preinfusion (trough) serum infliximab levels were generally associated with the need for dose escalation. Although some non‐responding patients seemed to clear infliximab more rapidly than others, increasing the dose of infliximab restored trough concentrations to levels sufficient for clinical response.
Infliximab concentrations of patients whose dose was increased were still generally lower than the concentrations seen for patients receiving 3 mg/kg who did not require dose escalation(s). It is noteworthy that there was no associated increase in the rate of adverse events for the patients receiving an escalated dose, which might be expected because the trough infliximab concentrations were generally not higher than those found in patients who did not receive dose escalation.
Patients who required dose escalation also had a slightly increased incidence of antibodies to infliximab (28.6%) compared with those who did not require dose escalation (19.5%); however, the difference was not statistically significant. An increased incidence of antibodies to infliximab in patients who required dose escalation was also reported in a smaller study (47% vs 29% for patients who did not require dose escalation).20
However, antibodies were not detected in the majority of patients who required dose escalation in either the previous study or in our study.
Although, patients who were positive for antibodies to infliximab had a slightly lower response to treatment than patients who were antibody negative or those who had an inconclusive antibody status, there was a positive relationship between dose and clinical response even among patients who had antibodies to infliximab. Therefore, increased doses of infliximab may, at least to some degree, offset a reduction in clinical response for patients with antibodies to infliximab.
In a recent study of patients who received infliximab for Crohn's disease,14
only detectable trough serum concentrations were a significant positive predictor of complete clinical remission among a variety of clinical and demographic variables, including antibody status. In the START study, trough median serum concentrations were low in patients who required dose escalation while the incidence of antibodies to infliximab was not statistically significantly increased. These results suggest that low trough serum concentrations may be a more important cause of lack of response or flare than antibodies to infliximab.
Seven patients received the maximum number of dose escalations allowed by the protocol (four dose increases to a total dose of 9 mg/kg). None of these seven patients met the criteria for response at any time during the study, even though their preinfusion (trough) infliximab serum concentrations at week 22 were well above 1 μg/ml. Only one of the seven patients was found to be positive for antibodies to infliximab, suggesting that antibodies were not the primary cause of the lack of response.
Although the numbers are small, the baseline characteristics for these seven patients suggest that inflammation was not a major part of their disease. Most of the patients had advanced disease (median disease duration 12.1 years). Possibly, these patients had secondary degenerative changes in their joints that contributed substantially to their symptoms. The median baseline CRP value (7 mg/l) was nearly normal and well below the median value for group 2 as a whole (24 mg/l). If these patients had signs and symptoms that were predominantly the result of secondary degenerative changes rather than active inflammation, it is not surprising that they did not respond to anti‐tumour necrosis factor α (TNFα) treatment despite receiving the highest dose and having sufficient serum infliximab concentrations. It is also possible that these patients have a subtype of RA that is not primarily mediated by TNFα.
As reported previously,15
an important finding of the START trial was that patients who received the unapproved induction regimen of 10 mg/kg infliximab in combination with MTX followed by maintenance doses of 10 mg/kg every 8 weeks had an increased risk of serious infections. The results of the current analysis show that most patients who received the induction regimen of 3 mg/kg followed by dose increases after week 22 (a regimen that is currently approved according to the product labelling in the United States)4
had clinical benefit without an increased risk of adverse events, including serious infections, when compared with patients who did not receive dose increases. However, this comparison is limited because the sample size was small and patients were not randomly assigned to receive dose escalation(s).
In this trial, TJC and SJC data were entered into an IVRS, which automatically calculated response or flare. Therefore, we assessed clinical response using joint count data only, rather than the typical response criteria such as ACR 20 and the Disease Activity Score. Joint counts have been shown to correlate with disease status, changes in the disease activity, progression of disease and mortality.21,22,23,24
Composite assessment criteria, such as ACR 20 and the Disease Activity Score, require acute phase reactant data, which were not available at the time of the patient visit when the need for dose escalation was determined. Acute phase reactant data could not have been used for determining the need for dose escalation while maintaining the blind. A recent study has shown that acute phase reactant data add little information to clinical assessments of disease activity.25
The authors recommended using the Clinical Disease Activity Index, which includes patient and evaluator global assessments in addition to TJC and SJC. However, this tool was neither validated nor available when our study was designed.
The START study was also limited by the 1‐year study duration. Patients who received a dose escalation at week 46 and did not respond at the following visit (week 54) could not receive further dose increases because the study ended. Some of these patients might have responded if the study had continued for longer than 1 year. In an extended study, patients would have been given the opportunity to receive additional dose increases or allowed more time to demonstrate a response.
In conclusion, some patients who did not respond to the initial dose of 3 mg/kg infliximab, or those who initially responded but subsequently flared, benefited from increased doses of infliximab without an increased risk of serious adverse events, including serious infections.