The current paradigm of infusing infliximab over 120 min was based on clinical trial data showing a tolerable incidence of side effects at this rate. A number of studies have shown that infusing at rates faster than the current practice is safe[2
]. Accelerated infusions of infliximab were safe in the population of patients in this study. There were no infusion reactions observed after delivering a total of 143 accelerated infusions over the course of this study. Only one patient had to revert to a 120-min infusion after receiving accelerated infusions. This instance was due to an increase in the infliximab dose, which mandated a subsequent 120-min infusion per the study protocol. Several patients repeated the intermediate rate infusions for various reasons; however, these reasons did not include suspected infusion reactions. Similar to prior studies[2
], this study provides further evidence that accelerated infusions of infliximab in IBD patients are well-tolerated regardless of dose, diagnosis, history of infusion reactions or treatment frequency.
Prior studies of faster infusion times have had different study populations. Our study is the first to use a dose of 7.5 mg/kg at faster rates and the largest number of patients receiving 10 mg/kg (n
= 16, 34.78% of the study population). Noticeably, there is only one prior study that included patients who received a 10 mg/kg dose (n
= 5, 2.8% of the study population)[5
]. Our study population is also notable for containing a majority of patients not receiving prophylaxis; among those getting pre-medications, there were a number of reasons for the prophylaxis. Some of our patients had a remote history of infusion reactions, while others had had treatment re-initiations; these patients all received pre-medications and none had infusion reactions with the accelerated protocol. Compared to other studies, our patient population also had a larger percentage of UC (19.6%) and overweight patients (56.5%).
This diversity in our patient population helps to broaden the evidence for safe administration of infliximab at faster rates. Higher doses of infliximab may be used and patients with prior infusion reactions or treatment re-initiations may still safely receive their treatments with a faster protocol.
The need for anti-TNF therapy is increasing. Several studies have suggested that a more aggressive “top-down” approach to CD, such as involving early adoption of regular doses of infliximab, is more effective than the traditional “step up” method of treatment[8
]. Using early aggressive therapy has been shown to decrease the need for surgery and reduce hospitalizations in patients with CD[8
], and prompt induction therapy in UC has been shown to promote mucosal healing, an important prognostic factor[9
]. The active ulcerative colitis trials 1 and 2, which investigated using infliximab as maintenance therapy for UC, demonstrated significant improvements in clinical response to treatment among patients with moderate-to-severe UC receiving infliximab, when compared to patients receiving conventional therapy[10
]. Whether the use of infliximab can reduce the rate of colectomy for UC patients is not currently known, but current data is promising[11
With the improvement in treatment options over the last decade comes the sobering fact that hospitalizations and inpatient charges for IBD, especially CD, have increased substantially: from 1998 to 2004, the hospitalization rate for CD-related health issues increased by 4.3% and total charges increased from $762 million to $1.33 billion[12
]. Considering the proven effectiveness of anti-TNF therapy and the rising incidence of IBD, it is likely that the number of patients on maintenance infliximab regimens will increase in the future. With rising health care costs and a system-wide heightened interest in efficiency and patient satisfaction, finding ways to streamline the delivery of this drug is a crucial step toward improving therapy for IBD. The cost savings from this protocol were significant. A total of $ 53 632 was saved over the course of this nine month period of time. This number represents a significant underestimate. With only 46 patients enrolled and many starting the accelerated protocol in the latter months of the study, this figure represents only a fraction of the cost-savings that could be obtained if the protocol were implemented in a wider and more consistent fashion. Cost savings for minimizing adverse events were not included in the estimate, which would contribute significantly to enhance the effectiveness of the infliximab infusions and thereby being in concert with the requirements of the Affordable Care Act.
Infliximab is not a benign drug and has the potential for serious side effects; compared to other biologics, it is the only drug with a significantly higher rate of adverse events than controls[13
]. Long-term effects include an increased risk of bacterial, viral, or fungal infections causing hospitalization[14
] and a theoretical, though unproven, increased risk of Hodgkin and non-Hodgkin lymphoma in adolescent and young adult males[15
]. Acute infusion reactions occur in 0.8% to 8.8% of infusions, affecting 10% to 23% of patients per year[16
]. Delayed infusion reactions occurred in roughly 2% of patients receiving infliximab over the course of a year[17
]. While this study did not examine the infectious or cancer risks, the complete lack of infusion reactions in our patients is a promising lead for making infliximab safer.
The incidence of infusion reactions to infliximab is highly related to the development of antibodies to the drug, known as human anti-chimeric antibodies (HACA)[18
]. Loss of response to treatment has also been observed in patients who develop these antibodies. Thus, the prevention of antibody formation is paramount in keeping infliximab as a safe and effective treatment for IBD patients. The development of these antibodies can be reduced by maintaining higher trough levels, having consistent dosing schedules[18
], and using pre-medications such as hydrocortisone[19
]. Additionally, the use of immunomodulators such as methotrexate has been shown to reduce antibody formation against infliximab in patients with rheumatoid arthritis[20
When reviewing the literature, Lee et al[2
] concluded in their study that 90% of the adverse reactions associated with infliximab infusions occur during the first eight infusions. Since our study population had a mean of 27 infusions prior to the initiation of the accelerated protocol we cannot easily compare our lack of reactions with the traditional infusion rates. However, considering the role that anti-infliximab antibodies play in the incidence of infusion reactions and treatment failure[18
], the infusion rate may be related to the development of these antibodies. Mori et al[21
] demonstrated that higher trough infliximab levels are associated with better outcomes. The serum concentration of infliximab measured one hour after each infusion approximates the maximum serum concentration (Cmax). Thus, we hypothesize that a more rapid attainment of Cmax may decrease the immune response to the drug. Future work could be directed toward monitoring the development of HACA among patients receiving infusions at different rates. Due to restrictions imposed by cost and insurance policies, this study did not analyze the infliximab serum level after 1 h infusions and it did not investigate the presence or absence of the antibodies toward infliximab.
Obese patients with CD also tend to have a higher incidence of perianal disease and more post-surgical complications[22
]. BMI has also been shown to be a significant factor in patients with CD since obesity itself may be a risk factor for CD[23
]. Treatment failures with infliximab in conditions such as rheumatoid arthritis[24
], ankylosing spondylitis[25
], and psoriasis[26
] are also more common in overweight and obese patients than in patients with normal BMIs. Over half of our patients were considered overweight by BMI and nearly a third were obese. With the need for effective treatment options being especially great for obese patients suffering from CD, it is reassuring to know that accelerated infliximab infusions were safe among this demographic, as demonstrated in this study.
There are a number of limitations to this study. There was no specifically defined control group to which the patients receiving faster infusions could be compared. The racial makeup of the study population was somewhat narrow as well. A few deviations from the study protocol occurred, with some patients receiving an intermediate-speed infusion multiple times due to physician preference rather than the clinical guidelines. However, despite these limitations, this study provides strong evidence for the benefits of implementing an accelerated infusion protocol for treating IBD patients on maintenance therapy. With such a protocol in place, costs to patients and hospitals in terms of both time and money would be decreased, patient safety and satisfaction may be increased, and a life-saving drug may be made more widely available. With additional data and further inquiry, faster infusions of infliximab may become the standard of care in the United States.