Serious Infections and Mortality in Association With Therapies for Crohn’s Disease: TREAT Registry
2006; Elsevier BV; Volume: 4; Issue: 5 Linguagem: Inglês
10.1016/j.cgh.2006.03.002
ISSN1542-7714
AutoresGary R. Lichtenstein, Brian G. Feagan, Russell D. Cohen, Bruce Salzberg, Robert H. Diamond, Donny M. Chen, Michelle L. Pritchard, William J. Sandborn,
Tópico(s)Immunodeficiency and Autoimmune Disorders
ResumoBackground & Aims: Long-term safety data for infliximab and other therapies in Crohn’s disease (CD) are needed. Methods: We prospectively evaluated patients for prespecified safety-related outcomes. Results: As of August 2004, 6290 patients were enrolled; 3179 received infliximab (5519 patient-years), 87% of whom received at least 2 infusions, and 3111 received other therapies (6123 patient-years). The mean length of follow-up evaluation was 1.9 years. More infliximab-treated patients had moderate-to-severe (30.8% vs 10.3%) or severe-fulminant (2.5% vs .6%) CD, and had surgical (17.5% vs 13.8%) or medical (14.4% vs 9.1%) hospitalizations in the previous year. More patients were taking prednisone (27.4% vs 16.1%), immunomodulators (49.4% vs 32.2%), or narcotic analgesics (9.8% vs 5.4%) when compared with those receiving other therapies (P < .001, all comparisons). The mortality rates were similar for infliximab- and non–infliximab-treated patients (.53 per 100 patient-years vs .43; relative risk, 1.24; 95% confidence interval [CI], .73–2.10). In multivariate logistic regression analysis, only prednisone was associated with an increased mortality risk (odds ratio [OR], 2.10; 95% CI, 1.15–3.83; P = .016). Although the unadjusted analysis showed an increased risk for infection with infliximab use, multivariate logistic regression analysis suggested that infliximab was not an independent predictor of serious infections (OR, .99; 95% CI, .64–1.54). Factors independently associated with serious infections included prednisone use (OR, 2.21; 95% CI, 1.46–3.34; P < .001), narcotic analgesic use (OR, 2.38; 95% CI, 1.56–3.63; P < .001), and moderate-to-severe disease activity (OR, 2.11; 95% CI, 1.10–4.05; P = .024). Conclusions: Mortality rates were similar between infliximab- and non–infliximab-treated patients. The increased risk for serious infection observed with infliximab likely was owing to disease severity and prednisone use. Background & Aims: Long-term safety data for infliximab and other therapies in Crohn’s disease (CD) are needed. Methods: We prospectively evaluated patients for prespecified safety-related outcomes. Results: As of August 2004, 6290 patients were enrolled; 3179 received infliximab (5519 patient-years), 87% of whom received at least 2 infusions, and 3111 received other therapies (6123 patient-years). The mean length of follow-up evaluation was 1.9 years. More infliximab-treated patients had moderate-to-severe (30.8% vs 10.3%) or severe-fulminant (2.5% vs .6%) CD, and had surgical (17.5% vs 13.8%) or medical (14.4% vs 9.1%) hospitalizations in the previous year. More patients were taking prednisone (27.4% vs 16.1%), immunomodulators (49.4% vs 32.2%), or narcotic analgesics (9.8% vs 5.4%) when compared with those receiving other therapies (P < .001, all comparisons). The mortality rates were similar for infliximab- and non–infliximab-treated patients (.53 per 100 patient-years vs .43; relative risk, 1.24; 95% confidence interval [CI], .73–2.10). In multivariate logistic regression analysis, only prednisone was associated with an increased mortality risk (odds ratio [OR], 2.10; 95% CI, 1.15–3.83; P = .016). Although the unadjusted analysis showed an increased risk for infection with infliximab use, multivariate logistic regression analysis suggested that infliximab was not an independent predictor of serious infections (OR, .99; 95% CI, .64–1.54). Factors independently associated with serious infections included prednisone use (OR, 2.21; 95% CI, 1.46–3.34; P < .001), narcotic analgesic use (OR, 2.38; 95% CI, 1.56–3.63; P < .001), and moderate-to-severe disease activity (OR, 2.11; 95% CI, 1.10–4.05; P = .024). Conclusions: Mortality rates were similar between infliximab- and non–infliximab-treated patients. The increased risk for serious infection observed with infliximab likely was owing to disease severity and prednisone use. Crohn’s disease (CD) is characterized by recurrent inflammation at any location in the gastrointestinal tract. The pharmacologic management of CD is based on the location, extent, and disease severity.1Rutgeerts P. van Assche G. Vermeire S. Optimizing anti-TNF treatment in inflammatory bowel disease.Gastroenterology. 2004; 126: 1593-1610Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 2Hanauer S.B. Drug therapy inflammatory bowel disease.N Engl J Med. 1996; 334: 841-848Crossref PubMed Scopus (449) Google Scholar, 3Podolsky D.K. Inflammatory bowel disease.N Engl J Med. 2002; 347: 417-429Crossref PubMed Scopus (3222) Google Scholar Therapeutic options include aminosalicylates, antibiotics, and immunosuppressive agents such as corticosteroids, antimetabolite immunomodulators (eg, 6-mercaptopurine, azathioprine, methotrexate), and infliximab. Infliximab has been proven to be efficacious in patients with either luminal4Targan S.R. Hanauer S.B. van Deventer S.J.H. et al.Crohn’s Disease cA2 Study GroupA short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease.N Engl J Med. 1997; 337: 1029-1035Crossref PubMed Scopus (3116) Google Scholar, 5Rutgeerts P. Feagan B.F. Lichtenstein G.R. et al.Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease.Gastroenterology. 2004; 126: 402-413Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar, 6Hanauer S.B. Feagan B.G. Lichtenstein G.R. et al.Maintenance infliximab for Crohn’s disease the ACCENT I randomized trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3726) Google Scholar, 7Rutgeerts P. D’Haens G. Targan S. et al.Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease.Gastroenterology. 1999; 117: 761-769Abstract Full Text Full Text PDF PubMed Scopus (1079) Google Scholar or fistulizing CD.8Present D.H. Rugeerts P. Targan S. et al.Infliximab for the treatment of fistulas in patients with Crohn’s disease.N Engl J Med. 1999; 340: 1398-1405Crossref PubMed Scopus (2506) Google Scholar, 9Sands B.E. Anderson F.H. Bernstein C.N. et al.Infliximab maintenance therapy for fistulizing Crohn’s disease.N Engl J Med. 2004; 350: 876-885Crossref PubMed Scopus (1921) Google Scholar The use of corticosteroids is associated with a high incidence of both short- and long-term side effects including Cushing’s syndrome, osteoporosis, diabetes, and infection.10Stuck A.E. Minder C. Frey F.J. Risk of infectious complication in patients taking glucocorticosteroids.Rev Infect Dis. 1989; 11: 954-963Crossref PubMed Scopus (692) Google Scholar, 11Yang Y.X. Lichtenstein G.R. Corticosteroids in Crohn’s disease.Am J Gastroenterol. 2002; 97: 803-823Crossref PubMed Google Scholar The use of immunomodulators is complicated by a delayed onset of action and side effects including bone marrow suppression, hepatotoxicity, and pancreatitis.12Sandborn W.J. A review of immune modifier therapy for inflammatory bowel disease azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate.Am J Gastroenterol. 1996; 91: 423-433PubMed Google Scholar Because both corticosteroids and immunomodulators have broad effects on the immune system, patients treated with these drugs may be at increased risk for serious or fatal infections.13Aucott J.N. Glucocorticoids and infection.Endocrinol Metab Clin North Am. 1994; 23: 655-670PubMed Google Scholar, 14Klein N.C. Go C.H. Cunha B.A. Infections associated with steroid use.Infect Dis Clin North Am. 2001; 15: 423-432Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Infliximab, which specifically targets tumor necrosis factor-α, also is associated with adverse events including infections. In large controlled clinical trials of infliximab in patients with CD, the percentage of patients with serious infections ranged from 4.0% to 4.6% and the mortality rate ranged from .7% to 1.3%.6Hanauer S.B. Feagan B.G. Lichtenstein G.R. et al.Maintenance infliximab for Crohn’s disease the ACCENT I randomized trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3726) Google Scholar, 9Sands B.E. Anderson F.H. Bernstein C.N. et al.Infliximab maintenance therapy for fistulizing Crohn’s disease.N Engl J Med. 2004; 350: 876-885Crossref PubMed Scopus (1921) Google Scholar The occurrence of infliximab-related adverse events, including serious opportunistic infections such as tuberculosis, listeriosis, histoplasmosis, and death, also has been documented in reports of open-label trials or retrospective trials.15Colombel J.F. Loftus E.V. Tremaine W.J. et al.The safety profile of infliximab in patients with Crohn’s disease the Mayo Clinic experience in 500 patients.Gastroenterology. 2004; 126: 19-31Abstract Full Text Full Text PDF PubMed Scopus (851) Google Scholar, 16Ricart E. Panaccione R. Loftus E.V. et al.Infliximab for Crohn’s disease in clinical practice at the Mayo Clinic the first 100 patients.Am J Gastroenterol. 2001; 96: 722-729Crossref PubMed Google Scholar, 17Cohen R.D. Tsang J.F. Hanauer S.B. Infliximab in Crohn’s disease first anniversary clinical experience.Am J Gastroenterol. 2000; 95: 3469-3477Crossref PubMed Google Scholar, 18Farrell R.J. Shah S.A. Lodhavia P.J. et al.Clinical experience with infliximab therapy in 100 patients with Crohn’s disease.Am J Gastroenterol. 2000; 95: 3490-3497Crossref PubMed Google Scholar Gastroenterologists remain concerned about the safety of CD treatments. Recognizing that registries are useful in evaluating safety by prospectively following-up large numbers of patients in real-world clinical settings for an extended time and representing cohorts of patients with the same disease who are treated with different drugs, we established a registry, The Crohn’s Therapy, Resource, Evaluation, and Assessment Tool (TREAT). The TREAT Registry is a large-scale, ongoing, observational registry that was designed to examine the safety of CD therapies, including infliximab. The TREAT Registry is a prospective, observational, multicenter, long-term registry of North American patients with CD. The registry was initiated in 1999 to evaluate the clinical safety outcomes of various treatment regimens, including infliximab, in the management of CD. Approximately 350 gastroenterologists from both community-based and academic practice settings were each to enroll up to 150 patients for a target enrollment of at least 5000 patients. Most physicians were identified from the membership list of the Crohn’s and Colitis Foundation Association. Patients were treated at the discretion of their physicians (ie, there was no defined treatment protocol). Physician participation in the registry could be withdrawn if patient enrollment requirements were not met, complete data were not submitted, a physician was leaving the practice, or if a physician elected to discontinue participation. The design of the TREAT Registry was approved by institutional review boards. All patients provided written informed consent. Physicians or their designees were paid a small honorarium on a per-patient basis as compensation for participating in the registry. Centocor, Inc. (Malvern, PA), the manufacturer of infliximab, sponsored the TREAT Registry, but all data were collected, collated, managed, and analyzed by Ovation Research Group (Highland Park, IL), an independent research organization, under the supervision and guidance of an Advisory Committee comprising several authors of this publication (G.R.L., B.G.F., R.D.C., B.A.S., and W.J.S.), and the TREAT medical monitor (R.H.D.). Patients must have had a diagnosis of CD and could not be participating in any clinical trial. Initially, patients younger than 18 years of age participated but the protocol subsequently was amended to limit enrollment to those age 18 years or older. In this ongoing registry, data are collected at enrollment and then on a semiannual basis (each January and July). Data collection will continue for a minimum of 5 years. Patient demographic information and physicians’ assessments of overall patient health were collected at enrollment. Physicians assessed disease severity (remission, mild-moderate, moderate-severe, or severe-fulminant) according to the American College of Gastroenterology Guidelines.19Hanauer S.B. Sandborn W. Practice Parameters Committee of the American College of GastroenterologyManagement of Crohn’s disease in adults.Am J Gastroenterol. 2001; 96: 635-643Crossref PubMed Google Scholar The follow-up data included assessment of disease severity, medication use, adverse events, dates of infliximab infusions, and outcomes of each infusion. The start and stop dates for other medications were not collected. Serious adverse events (SAEs) and changes in pregnancy status were collected as they occurred. Physicians were required to report SAEs within 24 hours of occurrence. A detailed description of the SAE including dates of onset and resolution; designation that the SAE was expected or unexpected; the seriousness and intensity of the SAE; the relationship of the SAE to the underlying CD; concomitant CD medications or surgical procedures for CD; and the treatment and outcome of the SAE, was collected. Baseline demographic and disease characteristics are summarized for the cohort of all patients combined and by treatment cohort. The cohort of patients who received infliximab within 12 weeks before enrollment, who were scheduled to receive infliximab within 30 days of enrollment, or who received infliximab at some other point in the registry was termed infliximab-treated patients. Because it is not possible to document infliximab administration before participation in the registry, only patients who met the criteria outlined previously are considered infliximab-treated. Patients who did not receive infliximab during the registry are termed other-treatments-only patients. Means and SDs were calculated for continuous variables (age, body mass index, and years between CD diagnosis and enrollment). Frequencies and percentages were generated for categoric outcomes (sex, race, involved intestinal segment[s], disease severity, use of immunomodulators, use of prednisone, use of narcotic analgesics, and health resource use). Corticosteroid use represented prednisone use exclusively; immunomodulator use represented the use of azathioprine, 6-mercaptopurine, and/or methotrexate. The Student t test was used to test for equality of means across treatment groups. The χ2 test was used to evaluate the association between treatment group and categoric variables. The primary analyses evaluated the rates of death and rates of serious infection among medication categories. If a patient had multiple serious infections, then the first serious infection was considered for this analysis. For each event, the rate of the events per 100 person-years was calculated for each medication category (infliximab vs other treatments) as the quotient of the total number of on-therapy events and patient-years of exposure to medication multiplied by 100. Two different definitions of exposure time were used: (1) total exposure to infliximab was defined as the time between the first infliximab infusion through the date of the last follow-up evaluation, and (2) exposure to infliximab was defined as having received infliximab within 3 months. Patients could accumulate exposure time in both infliximab and other-treatments-only categories, depending on infliximab start and stop dates. A Poisson regression analysis, accounting for within-patient correlations and as implemented by the GENMOD procedure in SAS (SAS Institute Inc., Cary, NC), tested for the differences in event rates between medication categories. In these analyses, a 2-sided P value of .05 was considered statistically significant. Multivariable regression modeling was used to explore the effects of baseline demographic characteristics (age, sex, race, diseased segment[s], disease severity, and years between diagnosis and enrollment in the TREAT Registry) and medication use as predictors of death and serious infection. For mortality analyses, CD medications, designated as ever used were obtained from all available 6-month periods ( January–June and July–December) that occurred between enrollment and the time of death. Medication use during the period in which the death occurred was included in this analysis. For analysis of serious infection, CD medication ever used was obtained from all available 6-month periods that occurred from enrollment through the period before the onset of the serious infection. Medication use during the period in which the infection occurred was not included in these analyses because medication start and stop dates were not collected for any medications other than infliximab. Therefore, it was unknown whether the medication was given in response to the event, or whether the medication caused the event. After examining the unadjusted models, demographic characteristics and medication ever used between enrollment and the event were included in a multivariate logistic model.20Hosmer D.W. Lemeshow S. Applied logistic regression. John Wiley & Sons, Inc, New York1998Google Scholar The Cox proportional hazards model with time-varying covariates also was used to assess the risk for an event in a given period based on drug use in the prior period. Because the core results identifying risk factors were consistent between the 2 approaches, results from the logistic regression are presented. The data collected through August 23, 2004, were analyzed using SAS software, version 8.02 or higher of the SAS System for Windows. No adjustments were made for multiple comparisons. Through August 2004, 6290 CD patients from 212 centers were enrolled from both community (82%) and academic (18%) centers. Most patients were female (58%) and Caucasian (89%), with an average age of 43 ± 14.7 years. The population was distributed almost equally between those who had been treated with infliximab (N = 3179, 50.5%) and those who had not. More than 85% of patients treated with infliximab had received at least 2 infusions. Among patients who received infliximab, a median of 5 (range, 1–32) infusions were received. Most patients (86%) received infliximab 5 mg/kg. Among the patients who had received at least 2 infusions, the average time between infusions was 61.2 ± 78.1 days. Approximately 16% of patients took budesonide and .5% of patients took cyclosporine at some point while enrolled in the registry. Infliximab-treated patients were younger than patients in the other-treatments-only group (P < .001), but did not differ with regard to sex or race (Table 1). Seventy-four patients who were younger than 18 years of age were enrolled, but their enrollment was discontinued when the protocol was amended to include only patients age 18 or older.Table 1Baseline Patient DemographicsCharacteristicAll patientsInfliximab treatedaInfliximab-treated patients are those patients who received infliximab within 12 weeks before enrollment, who were scheduled to receive infliximab within 30 days of enrollment, or who received infliximab at some other point in the registry.Other treatments onlyP valuebP value from t test (continuous variables) or χ2 test (categoric variables).Total patients, N6290 (100.0%)3179 (50.5%)3111 (49.5%)Age at enrollment, y Mean ± SD42.5 ± 14.740.3 ± 13.944.7 ± 15.3<.001Sex, N Female3619 (57.5%)1842 (57.9%)1777 (57.1%).24 Male2559 (40.7%)1289 (40.5%)1270 (40.8%) Unknown112 (1.8%)48 (1.5%)64 (2.1%)Race, N Caucasian5601 (89.0%)2823 (88.8%)2778 (89.3%).25 African American421 (6.7%)228 (7.2%)193 (6.2%) Asian24 (0.4%)15 (.5%)9 (.3%) Hispanic81 (1.3%)39 (1.2%)42 (1.4%) Other42 (.7%)22 (.7%)20 (.6%) Unknown/missing121 (1.9%)52 (1.6%)69 (2.2%)BMI at enrollment, kg/m2 Mean ± SD26.6 ± 16.626.6 ± 17.126.5 ± 16.1.91BMI, body mass index.a Infliximab-treated patients are those patients who received infliximab within 12 weeks before enrollment, who were scheduled to receive infliximab within 30 days of enrollment, or who received infliximab at some other point in the registry.b P value from t test (continuous variables) or χ2 test (categoric variables). Open table in a new tab BMI, body mass index. Patients in the infliximab-treated group differed significantly from patients in the other-treatments-only group with regard to intestinal segment(s) affected by disease, disease severity, health resource use in the year before enrollment, and medication use at enrollment (P < .0001 for all) (Table 2). Patients who received infliximab, compared with patients who received other treatments only, were more likely to have both their ileum and colon involved (43.2% vs 35.4%, respectively), and to have moderate-to-severe or severe-to-fulminant disease at enrollment (33.3% vs 10.9%, respectively). Hospitalization in the year before enrollment for either surgical (17.5% vs 13.8%) or medical (14.4% vs 9.1%) management also was more frequent among infliximab-treated patients compared with patients who received other treatments only. Patients in the infliximab-treated group were more likely to be receiving prednisone (27.4% vs 16.1%), immunomodulators (49.4% vs 32.2%), and narcotic analgesics (9.8% vs 5.4%) at enrollment.Table 2Baseline Disease CharacteristicsCharacteristicAll patientsInfliximab treatedaInfliximab-treated patients are those patients who received infliximab within 12 weeks before enrollment, who were scheduled to receive infliximab within 30 days of enrollment, or who received infliximab at some other time during the registry.Other treatments onlyP valuebP value from t test (continuous variables) or χ2 test (categoric variables).Total patients, N6290 (100.0%)3179 (50.5%)3111 (49.5%)Years between diagnosis and enrollment Mean ± SD10.8 ± 10.210.7 ± 9.810.9 ± 10.6.45Diseased segment(s), N Ileum only1806 (28.7%)799 (25.1%)1007 (32.4%)<.001 Colon only1767 (28.1%)895 (28.2%)872 (28.0%) Ileum and colon2475 (39.3%)1374 (43.2%)1101 (35.4%) Unknown/missing242 (3.8%)111 (3.5%)131 (4.2%)Disease severity, N RemissioncRemission refers to patients who are asymptomatic or without inflammatory sequelae and refers to patients who have responded to acute medical intervention or who have undergone surgical resection without evidence of residual disease. Patients requiring corticosteroids to maintain well-being are considered to be steroid-dependent and are not in remission.1535 (24.4%)387 (12.2%)1148 (36.9%)<.001 Mild/moderatedMild to moderate disease applies to ambulatory patients who are able to tolerate oral alimentation without manifestations of dehydration, toxicity (high fevers, rigors, prostration), abdominal tenderness, painful mass, obstruction, or >10% weight loss.3081 (49.0%)1592 (50.1%)1489 (47.9%) Moderate/severeeModerat-to-severe disease applies to patients who have failed to respond to treatment for mild to moderate disease or those with more prominent symptoms of fevers, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia.1299 (20.7%)979 (30.8%)320 (10.3%) Severe/fulminantfSevere-fulminant disease applies to patients with persistent symptoms despite the introduction of corticosteroids, or individuals presenting with high fever, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess.99 (1.6%)81 (2.5%)18 (.6%) Unknown/missing276 (4.4%)140 (4.4%)136 (4.4%)Health resource use in year before enrollment Surgical admissions, N985 (15.7%)557 (17.5%)428 (13.8%)<.001 Medical admissions, N741 (11.8%)459 (14.4%)282 (9.1%)<.001Medication use at enrollment Prednisone, N1372 (21.8%)870 (27.4%)502 (16.1%)<.001 Immunomodulators, N (%)2575 (40.9%)1572 (49.4%)1003 (32.2%)<.001 Narcotic analgesics, N (%)480 (7.6%)313 (9.8%)167 (5.4%)<.001a Infliximab-treated patients are those patients who received infliximab within 12 weeks before enrollment, who were scheduled to receive infliximab within 30 days of enrollment, or who received infliximab at some other time during the registry.b P value from t test (continuous variables) or χ2 test (categoric variables).c Remission refers to patients who are asymptomatic or without inflammatory sequelae and refers to patients who have responded to acute medical intervention or who have undergone surgical resection without evidence of residual disease. Patients requiring corticosteroids to maintain well-being are considered to be steroid-dependent and are not in remission.d Mild to moderate disease applies to ambulatory patients who are able to tolerate oral alimentation without manifestations of dehydration, toxicity (high fevers, rigors, prostration), abdominal tenderness, painful mass, obstruction, or >10% weight loss.e Moderat-to-severe disease applies to patients who have failed to respond to treatment for mild to moderate disease or those with more prominent symptoms of fevers, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia.f Severe-fulminant disease applies to patients with persistent symptoms despite the introduction of corticosteroids, or individuals presenting with high fever, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess. Open table in a new tab Patients were followed-up for a mean of 1.9 ± .96 years (median, 1.77 y; range, .5–4.91 y), and as of August 2004, approximately 79% of patients were participating actively in the registry. Patient discontinuations are outlined in Figure 1. Fifty-five (.87%) of the 6290 patients died. Of these 55 patients, 29 had received infliximab. Mortality rates were similar for patients who had received infliximab and those who had not: .53 per 100 patient-years vs .43 per 100 patient-years (relative risk [RR] [95% confidence interval (CI)] = 1.24 [.729–2.102]; P = .43). Similar rates were observed when patients were assessed by exposure to infliximab within the past 3 months. Sixteen patients died within 3 months of receiving an infliximab infusion (mortality rate per 100 patient-years, .41) compared with 39 who died who were not in this time frame (mortality rate, .50) (RR [95% CI] = .83 [.466–1.494]; P = .54). Without adjusting for other factors, patients who died were older (odds ratio [OR], 1.07 for each 1-year increase in age; P < .001) and had a longer duration of disease (OR, 1.06 for each 1-year increase in CD duration; P < .001). When medications were analyzed without adjusting for other factors, the use of prednisone (OR, 2.13; P = .007) and narcotic analgesics (OR, 1.84; P = .044) were associated with increased mortality. In the adjusted model, only age (OR, 1.07; P < .001), duration of CD (OR, 1.03; P = .006), and use of prednisone (OR, 2.10; P = .016) remained independent predictors of death. The use of infliximab was not a significant predictor of mortality in either the unadjusted or adjusted models (Table 3). The reported causes of death among patients are shown in a Table included in online supplementary materials (see Supplemental Table 1 at www.cghjournal.org).Table 3Predictors of MortalityPredictor variableAll patients(N = 6290)Deaths(N = 53aData representing patient status between registration and June 30, 2004, were used in the logistic regression analysis because this is the timeframe for which there is complete information or medication usage. Two patients died after June 30, 2004.)Unadjusted resultsAdjusted resultsOR (95% CI)cOR reported as OR per year increase in age.P valuebP value from Wald χ2 test.OR (95% CI)cOR reported as OR per year increase in age.P valuebP value from Wald χ2 test.Age Mean ± SD42 ± 14.759 ± 16.11.072 (1.053–1.092)cOR reported as OR per year increase in age.<.0011.072 (1.050–1.094)<.001Sex Male/unknown2671.94%—— Female3619.77%.825 (.480–1.418).49.733 (.415–1.293).28Race Non-Caucasian/unknown689.73%—— Caucasian5601.86%1.182 (.469–2.980).720.734 (.284–1.900).52Diseased segment(s) Ileum and colon24751.01%—— Ileum only1806.78%.766 (.397–1.477).43.891 (.449–1.768).74 Colon only1767.74%.726 (.371–1.424).35.866 (.419–1.789).70 Unknown242.41%.407 (.055–3.014).38.698 (.082–5.927).74Years between diagnosis and enrollment Mean ± SD11 ± 10.219 ± 15.71.062 (1.040–1.084)<.0011.030 (1.008–1.052).006Severity at baseline Remission1535.65%—— Mild3081.71%1.097 (.518–2.322).811.266 (.562–2.852).57 Moderate/severe13981.29%1.989 (.915–4.324).0832.256 (.900–5.653).083 Unknown2761.09%1.676 (.458–6.128).443.223 (.776–13.387).11Infliximab No3111.80%—— Yes3179.88%1.097 (.638–1.885).741.015 (.531–1.942).96Prednisone No3894.59%—— Yes23961.25%2.134 (1.237–3.683).0072.096 (1.147–3.832).016Immunomodulators No25261.03%—— Yes3764.72%.695 (.404–1.193).19.731 (.398–1.340).31Narcotic analgesics No5085.73%—— Yes12051.33%1.836 (1.018–3.312).0441.787 (.946–3.379).074a Data representing patient status between registration and June 30, 2004, were used in the logistic regression analysis because this is the timeframe for which there is complete information or medication usage. Two patients died after June 30, 2004.b P value from Wald χ2 test.c OR reported as OR per year increase in age. Open table in a new tab Among the 6253 patients who had adequate follow-up data for this analysis, 106 patients (1.70%) had a serious infection. Without adjusting for other factors, the rate of serious infections for the 69 patients who had received infliximab was significantly higher than that of 37 patients who were not treated with infliximab (1.37 per 100 patient-years vs .65; RR [95% CI], 2.15 [1.442–3.210]; P < .001). Without adjustment for other factors, there was a significantly higher rate of serious infection within 3 mon
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