Infliximab and Other Immunomodulating Drugs in Patients With Inflammatory Bowel Disease and the Risk of Serious Bacterial Infections
Risk of Serious Bacterial Infections?
S. Schneeweiss; J. Korzenik; D.H. Solomon; J. Lee; B. Bressler
Alimentary Pharmacology & Therapeutics. 2009;30(3):253-264. © 2009 Blackwell Publishing
Abstract
Background: There remain concerns about the safety of infliximab therapy in patients with inflammatory bowel disease (IBD).
Aim: To assess the association between the initiation of infliximab and other immunomodulating drugs and the risk of serious bacterial infection in the treatment of IBD.
Methods: We assembled a cohort study of patients with IBD, including Crohn's disease (CD) and ulcerative colitis (UC). All patients initiating an immunomodulating drug between January 2001 and April 2006 were identified in British Columbia from linked health care utilization databases. Exposure of interest was initiation of infliximab or corticosteroids compared with initiation of other immunosuppressive agents, including azathioprine, mercaptopurine (MP) and methotrexate (MTX). Outcome of interest was serious bacterial infections requiring hospitalization, including Clostridium difficile.
Results: Among 10 662 IBD patients, the incidence rate of bacteriaemia ranged from 3.8 per 1000 person-years (95% confidence interval 2.1–6.2) for other immunosuppressive agents to 7.4 (3.3–19.3) for infliximab with slightly higher rate for serious bacterial infections resulting in an adjusted relative risk 1.4 (0.47–4.24). Clostridium difficile infections occurred in 0/1000 (0–5.4) among 521 infliximab initiations and 14/1000 (10.6–18.2) for corticosteroids. Corticosteroid initiation tripled the risk of C. difficile infections (RR = 3.4; 1.9–6.1) compared with other immunosuppressant agents. This corticosteroid effect was neither dose-dependent nor duration-dependent. Bacteriaemia and other serious bacterial infections were not increased by corticosteroids or infliximab (5 events).
Conclusions: In a population-based cohort of patients with IBD, we found no meaningful association between infliximab and serious bacterial infections, although some subgroups had few events. Corticosteroid initiation increased the risk for C. difficile infections in these patients.
Background
Infliximab is a chimeric IgG4 monoclonal antibody targeting tumour necrosis factor α (TNF-α). More than 800,000 individuals and more than two million patient-years were estimated to have received treatment with Infliximab.[1] Infliximab's potential to alter the natural history of CD has created significant interest to widen the use of this medication for treating patients earlier in their disease course, thus potentially exposing many more patients to this medication. In a pivotal study examining the use of Infliximab as a maintenance therapy for treatment of CD, there was a significant reduction in disease-related hospitalizations and disease-related intra-abdominal surgeries in CD patients who received scheduled maintenance infusions of infliximab compared with those who only received episodic therapy.[2] However, several reports linked infliximab use with the incidence of bacterial and opportunistic infections.[3–6] More clarity on the potential risk of serious bacterial infections is necessary for a more informed benefit-risk assessment for use of infliximab in patients with inflammatory bowel disease (IBD). Clostridium difficile infections (C. difficile) are of particular concern in light of the impact this particular infection has on patients with IBD, including hospitalization rates and even potentially mortality, although there is currently no evidence of an increased risk for C. difficile infections by infliximab.
Outside the clinical trial setting, the first study to address the adverse event profile of Infliximab in IBD was a retrospective review of 500 consecutive patients treated with Infliximab at the Mayo Clinic in Rochester, Minnesota between October 1998 and October 2002.[3] The median follow-up for this cohort was 17 months (range, 0–48 months). Forty-three patients (8.6%) experienced a serious adverse event, 30 (6%) of which were thought to be related to Infliximab. Forty-eight patients (8.2%) acquired an infection although not all were classified as a serious adverse event. In a prospective, observational, multicentre registry of patients in North America treated with Infliximab (the TREAT registry), the rate of serious infections associated with Infliximab was 1.37 infections per 100 patient-years.[4]
The only population-based study addressing this important issue of safety with Infliximab consisted of a cohort of 217 patients with inflammatory bowel disease (IBD) in Stockholm County, Sweden between January 1999 and April 2001.[5] A total of 11 medical centres contributed to the study; these centres were the only ones administering Infliximab during this time period. Forty-one patients (18.9%) experienced a serious event from January 1999 to April 2001. Eighteen of these patients' serious events were infections, 7 of them were in the post-operative period. Two patients died of sepsis while on infliximab. As the use of Infliximab is restricted to specific centres in Sweden, their complication rates may differ from that in other countries where such a restriction is not in place.
The risk of Infliximab treatment to cause serious infections, including C. difficile infections, in routine care of patients with IBD compared to other immunomodulating medications remains largely unknown. We sought to evaluate the comparative safety of infliximab in patients with IBD using linked administrative databases from British Columbia, Canada.
Methods
Data Source and Patients
We conducted a cohort study of British Columbia (BC) residents 18 years and older with Crohn's disease (CD) or ulcerative colitis (UC) who initiated use of a range of immunomodulating drugs, including Infliximab, glucocorticoids and other drugs, from January 2001 to April 2006. Patients were identified in linked health care utilization databases from the BC Ministry of Health. This database contains information on all physician services (Medical Services Plan), hospitalizations with up to 25 diagnostic codes, and all prescription drug dispensings were recorded by the province-wide PharmaNet database. We further linked vital status information from the BC vital statistics agency. Underreporting and misclassification appear minimal because of the electronic data entry of all drug dispensings and hospital diagnoses showed good specificity and completeness.[7]
Patients with IBD were identified by having at least five health care encounters with a recorded diagnosis of IBD (ICD-9 codes 555.x and 556.x). This definition was relaxed to three recorded diagnoses of IBD if patients were residing in BC for days or shorter. This definition has been developed and validated for identifying IBD cases in administrative databases using the Manitoba Health Database that is very similar to the British Columbia linked administrative databases in its population coverage and data completeness.[8] Patients were considered for this study only after the fifth (or third) occurrence of a diagnostic code for IBD. Patients with any cancer (except non-melanoma skin cancer) or HIV/AIDS were identified by at least two physician services with a corresponding ICD-9 diagnosis in the prior 365 days and were excluded from the analysis.
Within this cohort of patients with IBD, we identified each patient's date of initiating immunomodulating therapy (cohort entry date). To be categorized as initiating a specific therapy, we required at least 365 days without use of that agent before the cohort entry date. Patients could initiate use of more than one immunomodulating therapy as well as multiple courses of the same agent during the study period if each initiation fulfilled the 365 days washout period. Within each course of therapy, follow-up time started at the date of cohort entry. Follow-up ended at the earliest of (1) discontinuation of the drug, (2) first occurrence of a study infection, (3) end of the study period, or (4) death.
All traceable personal identifiers were removed from the dataset prior to analysis to protect patient confidentiality. The Institutional Review Board of the Brigham and Women's Hospital approved this study and signed data use agreements were in place.
Drug Exposure
Study drug categories included initiation of infliximab therapy, oral glucocorticoids and 'other immunosuppressive agents' (methotrexate, azathioprine, mercaptopurine), which served as the reference drug exposure. We further identified a minimally treated patient group consisting of initiators of aminosalicylate or patients with a qualifying diagnosis of IBD, but without any of the treatments listed above. This group was not included in the analysis because patients may have milder expression of their disease and including these patients would increase the potential for confounding by discrepancies in disease severity. The index date for each drug was the date of first dispensing. If patients started two of the study drugs on the same day, each would be considered as episodes of treatment initiation and the other drug would be considered a concurrently used immunomodulating agent.
To allow for continued immunosuppressive effects of these drugs even after dosing may have stopped, we calculated the end of exposure based on approximate half-lives. MTX, azathioprine, mercaptopurine and glucocorticoids were assigned 21 days of exposure beyond the days supply.[9] We assumed that each infliximab infusion was affecting the immune system for up to 126 days, which we defined as our exposure-risk window.[9]
Risk of Serious Bacterial Infections?
S. Schneeweiss; J. Korzenik; D.H. Solomon; J. Lee; B. Bressler
Alimentary Pharmacology & Therapeutics. 2009;30(3):253-264. © 2009 Blackwell Publishing
Abstract
Background: There remain concerns about the safety of infliximab therapy in patients with inflammatory bowel disease (IBD).
Aim: To assess the association between the initiation of infliximab and other immunomodulating drugs and the risk of serious bacterial infection in the treatment of IBD.
Methods: We assembled a cohort study of patients with IBD, including Crohn's disease (CD) and ulcerative colitis (UC). All patients initiating an immunomodulating drug between January 2001 and April 2006 were identified in British Columbia from linked health care utilization databases. Exposure of interest was initiation of infliximab or corticosteroids compared with initiation of other immunosuppressive agents, including azathioprine, mercaptopurine (MP) and methotrexate (MTX). Outcome of interest was serious bacterial infections requiring hospitalization, including Clostridium difficile.
Results: Among 10 662 IBD patients, the incidence rate of bacteriaemia ranged from 3.8 per 1000 person-years (95% confidence interval 2.1–6.2) for other immunosuppressive agents to 7.4 (3.3–19.3) for infliximab with slightly higher rate for serious bacterial infections resulting in an adjusted relative risk 1.4 (0.47–4.24). Clostridium difficile infections occurred in 0/1000 (0–5.4) among 521 infliximab initiations and 14/1000 (10.6–18.2) for corticosteroids. Corticosteroid initiation tripled the risk of C. difficile infections (RR = 3.4; 1.9–6.1) compared with other immunosuppressant agents. This corticosteroid effect was neither dose-dependent nor duration-dependent. Bacteriaemia and other serious bacterial infections were not increased by corticosteroids or infliximab (5 events).
Conclusions: In a population-based cohort of patients with IBD, we found no meaningful association between infliximab and serious bacterial infections, although some subgroups had few events. Corticosteroid initiation increased the risk for C. difficile infections in these patients.
Background
Infliximab is a chimeric IgG4 monoclonal antibody targeting tumour necrosis factor α (TNF-α). More than 800,000 individuals and more than two million patient-years were estimated to have received treatment with Infliximab.[1] Infliximab's potential to alter the natural history of CD has created significant interest to widen the use of this medication for treating patients earlier in their disease course, thus potentially exposing many more patients to this medication. In a pivotal study examining the use of Infliximab as a maintenance therapy for treatment of CD, there was a significant reduction in disease-related hospitalizations and disease-related intra-abdominal surgeries in CD patients who received scheduled maintenance infusions of infliximab compared with those who only received episodic therapy.[2] However, several reports linked infliximab use with the incidence of bacterial and opportunistic infections.[3–6] More clarity on the potential risk of serious bacterial infections is necessary for a more informed benefit-risk assessment for use of infliximab in patients with inflammatory bowel disease (IBD). Clostridium difficile infections (C. difficile) are of particular concern in light of the impact this particular infection has on patients with IBD, including hospitalization rates and even potentially mortality, although there is currently no evidence of an increased risk for C. difficile infections by infliximab.
Outside the clinical trial setting, the first study to address the adverse event profile of Infliximab in IBD was a retrospective review of 500 consecutive patients treated with Infliximab at the Mayo Clinic in Rochester, Minnesota between October 1998 and October 2002.[3] The median follow-up for this cohort was 17 months (range, 0–48 months). Forty-three patients (8.6%) experienced a serious adverse event, 30 (6%) of which were thought to be related to Infliximab. Forty-eight patients (8.2%) acquired an infection although not all were classified as a serious adverse event. In a prospective, observational, multicentre registry of patients in North America treated with Infliximab (the TREAT registry), the rate of serious infections associated with Infliximab was 1.37 infections per 100 patient-years.[4]
The only population-based study addressing this important issue of safety with Infliximab consisted of a cohort of 217 patients with inflammatory bowel disease (IBD) in Stockholm County, Sweden between January 1999 and April 2001.[5] A total of 11 medical centres contributed to the study; these centres were the only ones administering Infliximab during this time period. Forty-one patients (18.9%) experienced a serious event from January 1999 to April 2001. Eighteen of these patients' serious events were infections, 7 of them were in the post-operative period. Two patients died of sepsis while on infliximab. As the use of Infliximab is restricted to specific centres in Sweden, their complication rates may differ from that in other countries where such a restriction is not in place.
The risk of Infliximab treatment to cause serious infections, including C. difficile infections, in routine care of patients with IBD compared to other immunomodulating medications remains largely unknown. We sought to evaluate the comparative safety of infliximab in patients with IBD using linked administrative databases from British Columbia, Canada.
Methods
Data Source and Patients
We conducted a cohort study of British Columbia (BC) residents 18 years and older with Crohn's disease (CD) or ulcerative colitis (UC) who initiated use of a range of immunomodulating drugs, including Infliximab, glucocorticoids and other drugs, from January 2001 to April 2006. Patients were identified in linked health care utilization databases from the BC Ministry of Health. This database contains information on all physician services (Medical Services Plan), hospitalizations with up to 25 diagnostic codes, and all prescription drug dispensings were recorded by the province-wide PharmaNet database. We further linked vital status information from the BC vital statistics agency. Underreporting and misclassification appear minimal because of the electronic data entry of all drug dispensings and hospital diagnoses showed good specificity and completeness.[7]
Patients with IBD were identified by having at least five health care encounters with a recorded diagnosis of IBD (ICD-9 codes 555.x and 556.x). This definition was relaxed to three recorded diagnoses of IBD if patients were residing in BC for days or shorter. This definition has been developed and validated for identifying IBD cases in administrative databases using the Manitoba Health Database that is very similar to the British Columbia linked administrative databases in its population coverage and data completeness.[8] Patients were considered for this study only after the fifth (or third) occurrence of a diagnostic code for IBD. Patients with any cancer (except non-melanoma skin cancer) or HIV/AIDS were identified by at least two physician services with a corresponding ICD-9 diagnosis in the prior 365 days and were excluded from the analysis.
Within this cohort of patients with IBD, we identified each patient's date of initiating immunomodulating therapy (cohort entry date). To be categorized as initiating a specific therapy, we required at least 365 days without use of that agent before the cohort entry date. Patients could initiate use of more than one immunomodulating therapy as well as multiple courses of the same agent during the study period if each initiation fulfilled the 365 days washout period. Within each course of therapy, follow-up time started at the date of cohort entry. Follow-up ended at the earliest of (1) discontinuation of the drug, (2) first occurrence of a study infection, (3) end of the study period, or (4) death.
All traceable personal identifiers were removed from the dataset prior to analysis to protect patient confidentiality. The Institutional Review Board of the Brigham and Women's Hospital approved this study and signed data use agreements were in place.
Drug Exposure
Study drug categories included initiation of infliximab therapy, oral glucocorticoids and 'other immunosuppressive agents' (methotrexate, azathioprine, mercaptopurine), which served as the reference drug exposure. We further identified a minimally treated patient group consisting of initiators of aminosalicylate or patients with a qualifying diagnosis of IBD, but without any of the treatments listed above. This group was not included in the analysis because patients may have milder expression of their disease and including these patients would increase the potential for confounding by discrepancies in disease severity. The index date for each drug was the date of first dispensing. If patients started two of the study drugs on the same day, each would be considered as episodes of treatment initiation and the other drug would be considered a concurrently used immunomodulating agent.
To allow for continued immunosuppressive effects of these drugs even after dosing may have stopped, we calculated the end of exposure based on approximate half-lives. MTX, azathioprine, mercaptopurine and glucocorticoids were assigned 21 days of exposure beyond the days supply.[9] We assumed that each infliximab infusion was affecting the immune system for up to 126 days, which we defined as our exposure-risk window.[9]