Supported in part by the American Gastroenterological Association Foundation Student Research Fellowship Award and the Digestive Disease Research Core Center of the University of Chicago (DK42086).
Predictors of adalimumab dose escalation in patients with crohn's disease at a tertiary referral center†
Article first published online: 31 MAR 2011
Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 18, Issue 1, pages 10–16, January 2012
How to Cite
Cohen, R. D., Lewis, J. R., Turner, H., Harrell, L. E., Hanauer, S. B. and Rubin, D. T. (2012), Predictors of adalimumab dose escalation in patients with crohn's disease at a tertiary referral center. Inflamm Bowel Dis, 18: 10–16. doi: 10.1002/ibd.21707
- Issue published online: 11 DEC 2011
- Article first published online: 31 MAR 2011
- Manuscript Accepted: 15 FEB 2011
- Manuscript Received: 10 JAN 2011
- Crohn's disease;
- inflammatory bowel disease;
- anti-TNFα therapy;
Pivotal trials for adalimumab (ADA) demonstrated effectiveness versus placebo for induction and maintenance of remission in moderate to severely active Crohn's disease (CD). Although the approved maintenance regimen in the U.S. is 40 mg subcutaneously every 14 days, some patients require dose-escalation ([DE] either an increase in the delivered dose or decrease in the interval of treatment). Our objective was to determine which patient-, disease-, and therapy-related factors were associated with DE in CD patients treated with ADA.
This retrospective medical record review of patients included all patients treated with ADA for CD at the University of Chicago Inflammatory Bowel Disease Center between 2003 and 2008. Patient-related factors, disease-related factors, and therapy-related factors were analyzed. Survival and logistic regression analyses were performed.
In all, 75 patients treated with ADA between December 2003 and June 2008 were identified. Thirty-one subjects (41%) required DE (32% male, median age 37.6, median disease duration 22.7 years) after a median 20 weeks of therapy (range 2–75). Patient-, clinical-, and therapy-related factors were similar between DE and non-DE. Need for DE was predicted by a family history of inflammatory bowel disease (IBD) (P = 0.0187). Time to DE was predicted by male gender, isolated colonic disease, and smoking history (all P < 0.05); however, only male gender was an independent predictor of time to DE.
In all, 41% of CD patients required ADA DE, with shorter time to DE in smokers, men, and patients with isolated colonic disease. Patients, caregivers, and insurers should anticipate DE when utilizing ADA in CD. (Inflamm Bowel Dis 2011;)
Approximately 1.5 million people in North America suffer from inflammatory bowel disease (IBD), of which ≈650,000 have Crohn's disease (CD).1 In 1998 the Food and Drug Administration (FDA) approved the first biologic agent for the treatment of CD, infliximab (IFX). Production of tumor necrosis factor-α (TNF-α) is increased in IBD and is implicated in the pathogenesis of mucosal inflammation.2 IFX, a chimeric (25% murine/75% human) IgG1 antibody directed against TNF-α is approved for induction and maintenance therapy of moderate to severely active CD, as well as for the treatment of fistulous disease.3–7 However, despite its effectiveness, IFX use has been associated with loss of response and immunogenicity.8 More recently, additional biologic agents targeting TNF-α have been approved by the FDA, including adalimumab (ADA) and certolizumab pegol.
ADA is a fully human, recombinant IgG1 monoclonal antibody directed against TNF-α, approved by the FDA in 2007 for the induction and maintenance of remission of moderate to severely active CD in adult patients.9–11 ADA is also useful in patients who have lost response to IFX.12 Unlike IFX, which is dosed intravenously and based on body weight, ADA is administered as a subcutaneous injection and has been studied and approved for uniform dosing. Despite this approved and labeled dosing, 27% of patients in the maintenance trial of ADA initially randomized to every other week dosing experienced relapse of symptoms and required weekly dosing.11, 13, 14 Dose escalation rates as high as 79% have been found in CD patients receiving ADA after loss of response or intolerance to IFX.13 However, there exists a paucity of research examining factors that predict the need for this dose escalation. Given the morbidity associated with inappropriate dosing and the high cost of this biologic agent, determining predictors of dose escalation has important clinical and economic implications. This study was designed to review the clinical course of all CD patients at the University of Chicago Inflammatory Bowel Disease Center who received ADA and assess the patient-, disease-, and therapy-related factors that predict the need for dose escalation.
PATIENTS AND METHODS
This study compared variables between adult CD patients treated with ADA who required dose escalation (DE) and those who did not require dose escalation (NDE) for treatment of their CD, and also evaluated the relationship between these variables to the elapsed time until dose escalation was initiated in the DE group. The study was approved by the Institutional Review Board at the University of Chicago Medical Center.
Patients were identified who were treated with ADA for CD between December 2003 and June 2008. Inclusion criteria included the following: 1) age greater than 17 years; 2) a histological diagnosis of CD; and 3) active treatment at the University of Chicago Inflammatory Bowel Disease Center for a minimum of 3 months prior to the study period. The patients studied were from the practices of four different University of Chicago trained gastroenterologists who specialize in the treatment of IBD (R.C., L.H., S.H., and D.R.). Patients who had previously received other anti-TNF-α agents were included in the analysis. Patients who had been enrolled in previous placebo-controlled trials utilizing adalimumab were not included in this analysis.
Clinical, Demographic, and Laboratory Data
Clinic and endoscopy notes, pathology reports, and laboratory data from 1997 to the present were obtained from the hospital's electronic medical record database. Permanent hospital charts containing clinic notes and hospital discharge summaries were also reviewed. These records were searched for the following patient-related factors: height, weight, race, gender, and age at diagnosis. If only a year of diagnosis was identified, the date June 15th was selected. If only a year and a month was identified, then the first day of that month was used. Pertinent disease-related factors included: location of disease, presence and location of fistulae, duration of disease (from diagnosis to most recent clinic date), and C-reactive protein values.
The efficacy of ADA for luminal CD was judged by their treating physician on a 3-point scale: 1) “Remission/complete response/no or rare symptoms”; 2) “Response” (improved but not remission criteria); or 3) “Minimal/no response/worsened.” The efficacy in the treatment of Crohn's fistulous disease was ranked by the treating physician on a 4-point scale: 1) “not improved”; 2) “improved but not closed”; 3) “closed”; 4) “closed but then reopened.” In instances where the data were not clearly defined in the patient chart, the attending physician or dedicated outpatient IBD nurse was contacted to provide the missing information.
The following therapy-related factors were recorded: need for dose escalation, time to dose escalation, reason for escalation, and concomitant medications (i.e., steroids and immunomodulator agents). Prior use of another anti-TNF agent (and the timing) was also recorded. The need for dose escalation was defined on an individual basis by the primary gastroenterologist. A dose escalation was defined as an increase in dosing frequency (e.g., 40 mg SQ every week) or dosage (e.g., 80 mg SQ).
Statistical analysis was performed using 2-sided Fisher's exact test or chi-square test with Yates correction for nominal variables. Student's t-test was used for ordinal variables with a normal distribution; the rank-sum test was used for those variables without a normal distribution. P < 0.05 was considered statistically significant. Univariate and multivariate analyses were performed (Stata, College Station, TX) to detect variables independently associated with dose escalation of ADA. Survival curves were performed using the methodologies of Kaplan and Meier to determine differences in need for or timing of dose escalation. Sample size calculations predicted that our 75 patient study population would provide a statistical power of 98.6% at a 0.05 α-level to detect a 20% difference in dose escalation between two groups, with a baseline dose-escalation rate assumed to be 20%. The statistical power fell to 97.4% at a 0.025 α-level.
There were 75 patients identified who received ADA for the treatment of CD from December 2003 to June 2008. Their median age was 38.3 years; 43% were male, and their median duration of disease was 18.9 (range 0.9–35.1 years). Immunomodulator use was present in 40% at the time of initiation of ADA, while 21% were on corticosteroids. More than two-thirds had received prior anti-TNF therapy (69%, all with IFX); 50% of these patients had lost response to their IFX. Human antichimeric antibodies were measured in 9.6% of those who discontinued therapy (although they were not checked in all such patients); infusion reactions resulting in IFX discontinuation were recorded in 11.5%. Sixty-five percent of patients underwent at least one surgical operation for CD before, during, or after initiation of ADA (Table 1). Seventy-three of the 75 patients (97%) had data regarding luminal disease outcomes; 32 patients had data regarding fistulous disease outcomes (43%). All of the fistula patients also had luminal disease.
|Mean age (years) at first dose adalimumab [range]||38.3 [17.4-62.4]|
|Male gender||32 (43%)|
|Mean BMI [range]||25.2 [15.8-37.8]|
|Duration of disease (years)||18.9|
|Location of disease|
|• Isolated proximal*||2 (3%)|
|• Isolated small bowel||6 (8%)|
|• Isolated colonic||15 (20%)|
|• Proximal + ileal and/or colonic||15 (20%)|
|• Ileocolonic||37 (49%)|
|Perianal disease||32 (43%)|
|Fistulizing disease||32 (43%)|
|Family history||21 (28%)|
|Extraintestinal manifestations||19 (27%)|
|Smoking history||25 (36%)|
|Prior anti-TNF therapy||52 (69%)|
|• Loss of response||26 (50%)|
|Steroids at initiation||15 (21%)|
|Immunomodulator use||30 (40%)|
Overall Remission and Response Rates
Overall, 38/73 (52%) of the patients achieved a clinical remission of luminal disease after initiation of ADA and 66/73 (90%) experienced a beneficial clinical response. For fistulous disease, remission was attained in 19/32 (59%) and response in 26/32 (81%).
In a univariate analysis, isolated ileal disease was an independent predictor of luminal remission after ADA (100% versus 48%, P = 0.026). This predictor was also significant in a multivariate analysis after controlling for gender (P = 0.014), gender and age together (P = 0.018), family history (P = 0.018), and prior anti-TNF-α therapy (P = 0.017).
In a univariate analysis, duration of disease at first dose of ADA (20.65 versus 7.04 years, P = 0.0003) was the only independent predictor of luminal response to ADA. However, in a multivariate analysis duration of disease was not an independent predictor after controlling for age or gender. Both a family history of IBD (100% versus 86%, P = 0.098) and smoking history (100% versus 84%, P = 0.086) approached significance as predictors of luminal response. In a multivariate analysis, family history was not predictive of luminal response after controlling for gender or disease duration. However, in a multivariate analysis smoking history was an independent predictor of luminal response after controlling for gender (P = 0.048), family history (P = 0.031), family history and gender together (0.032), but not after controlling for age (P = 0.184).
Fistula Remission and Response
In a univariate analysis, duration of disease at first dose of ADA approached significance as a predictor of fistula response (21.56 versus 10.22 years, P = 0.078). In a multivariate analysis, this variable was not predictive of fistula response after controlling for age or gender. There were no variables predictive of fistula remission by either univariate or multivariate analysis.
Thirty-one patients (41%) required ADA DE during this time period while 44 (59%) maintained the same dose of ADA (NDE). The median time to dose escalation was 20 weeks (range 2–75). (Fig. 1) The comparisons between the DE and NDE are detailed below and in Table 2.
|Variable||Dose Escalators||Nondose Escalators||P|
|Age at first dose adalimumab (mean [range])||37.6 [17.8–62.1]||38.8 [17.4–62.4]||0.343|
|Male gender||10 (33.3%)||22 (48.9%)||0.182|
|BMI (mean [range])||26.1 [16.0–37.8]||24.5 [15.8–35.7]||0.838|
|Duration of disease (yrs)||22.7||16.2||0.853|
|Location of disease||0.602|
|• Isolated ileal||3 (10%)||3 (6.7%)|
|• Isolated colonic||8 (27%)||7 (15.6%)|
|• Ileocolonic||12 (40%)||25 (56%)|
|Perianal disease||14 (45%)||18 (41%)||0.483|
|Fistulizing disease||21 (48%)||11 (35%)||0.391|
|Family history||13 (42%)||8 (18%)||0.018ab|
|Extraintestinal manifestations||7 (24%)||12 (29%)||0.678|
|Smoking history||9 (31%)||16 (39%)||0.492|
|Prior anti-TNF therapy||23 (77%)||28 (64%)||0.234|
|• Loss of response||14 (61%)||12 (44%)|
|Steroids at initiation||5 (18%)||10 (23%)||0.586|
|Immunomodulator use||13 (43%)||17 (38%)||0.630|
|Surgery||19 (61%)||29 (66%)||0.366|
There were no significant differences in age at first dose of ADA, gender, body mass index (BMI), or smoking status between the DE and NDE groups (Table 2). Patients in the DE group were more likely to have a positive family history of IBD than those in the NDE group (42% versus 18%; P = 0.018).
The average duration of disease and length of follow-up after initiation of ADA did not differ significantly between groups (Table 2). The majority of patients in both groups had ileocolonic CD, followed by isolated colonic, isolated ileal, and isolated upper gastrointestinal (GI; disease proximal to the ileum) involvement. These trends in disease location were similar when DE and NDE populations were analyzed separately. More than one-third of patients in both groups were affected by perianal disease and fistulas. The median C-reactive protein (CRP) value prior to therapy did not differ significantly between groups.
No significant differences were found after analyzing therapy-specific variables (Table 2). More than half of both groups had received prior therapy with IFX. Similarly, steroid and immunomodulator use was similar between patients requiring dose escalation and those who did not require intensification of therapy. Four subjects in the NDE group and two subjects in the DE group required hospitalization while receiving ADA. Additionally, four subjects in the NDE group and six subjects in the DE group required surgery after initiation of ADA.
A time-to-event analysis was performed to examine whether patients who previously received IFX required ADA dose escalation compared to patients who had never received therapy with IFX. No significant difference was observed in time to first dose escalation between these groups (Fig. 2). The median time to dose escalation was 26 weeks (range 4–75) for patients previously treated with IFX, and 16 weeks (range 2–51) for those who had never had prior IFX therapy (P = 0.85 log rank test).
Logistic Regression Analysis
Two separate logistic regressions were performed: the first aimed to determine factors predictive of the need for dose escalation while the second aimed to determine factors predictive of time to first dose escalation.
Predictors of Need for Dose Escalation
In this univariate analysis, the only variable that predicted the need for dose escalation was a positive family history of IBD (42% versus 18%; P = 0.018; Table 2). Neither age, gender, BMI, disease duration, disease location, presence of perianal or fistulizing disease, smoking, steroid use, immunomodulator use, prior anti-TNF use, nor previous surgery were predictive of the need for dose escalation. By multivariate analysis, family history of IBD was still predictive of the need for DE after controlling for age (P = 0.034), age and gender (P = 0.045), prior anti-TNF alpha use (P = 0.029), and prior anti-TNF-α use and age (0.048). The P-value rose to 0.06 after controlling for age, gender, and prior anti-TNF-α use.
Predictors of Time to Dose Escalation
In a separate univariate analysis, male gender (12.1 versus 36.4 weeks; P = 0.0012), smoking history (15.8 versus 36.3 weeks; P = 0.013), and colonic-only involvement (13.2 versus 34.6 weeks; P = 0.0062) were significantly associated with earlier time to DE. Neither age, BMI, disease duration, disease location, presence of perianal or fistulizing disease, steroid use, immunomodulator use, prior anti-TNF use, nor previous surgery were predictive of the need for dose escalation. A multivariate analysis controlling for these variables revealed that male gender was independent of disease location (P = 0.038), but not independent of age at first dose of ADA or smoking status. Neither disease location nor smoking status was independent of gender in predicting time to first DE.
Biologic therapies have revolutionized therapy for IBD and rheumatic diseases. In clinical practice for treatment of IBD, these agents are often used in a “bottom-up” approach after patients have failed prior immunosuppressive therapies including aminosalicylates, corticosteroids, and other immunomodulating agents. A “top-down” approach utilizes biologic agents earlier in management before patients have proven to be refractory to other agents, but it is unclear which patients benefit from this approach.15 The introduction of ADA for induction and maintenance therapy for CD provided another option for patients with moderate-to-severe disease and also for patients refractory to or intolerant of IFX.
Prediction models, such as Ranson's criteria for acute pancreatitis, are used to detect patients destined for worse outcomes who require more aggressive initial therapy.16 It would be useful to predict which patients with moderate-to-severe CD are most likely to benefit from specific therapies to enhance success rates while minimizing medication or disease-related adverse events. This is of particular interest with the biological therapies, whereby concerns over drug costs and potential serious adverse events could be balanced if one could determine those patients most likely to benefit from therapy.
Previous authors have created such models for patients with severe IBD. Travis et al17 studied 51 patients with severe ulcerative colitis (UC) and showed that 30/41 patients had an incomplete response to steroids or required surgery. These investigators determined that at the timepoint of the 3rd day of hospitalization and treatment with corticosteroids, patients experiencing greater than eight bowel movements per day, and those with the combination of a CRP >45 and 3–8 bowel movements per day had an 85% likelihood of undergoing colectomy. Rowe et al18 showed that a high band count was a significant predictor of response to cyclosporine in a retrospective review of severe, steroid-resistant UC.
Although there have been some investigations into predictors of responses to IFX, there is a paucity of research examining the incidence of or predictive factors for dose escalation of ADA or other anti-TNF-α agents in patients with IBD or other inflammatory disorders. Ferrante et al19 studied 100 patients who had received IFX for UC and found that responders were younger (median age 35.7) than nonresponders median age 41.6. In a multicenter cohort of CD patients from France, Laharie et al20 found that isolated colonic involvement was a significant predictive factor of sustained response to IFX. In a population in which ADA was used to treat psoriasis, 30% (12/40) of patients receiving ADA 40 mg every other week (eow) required dose escalation.21 Rudwaleit et al22 studied a population of patients with ankylosing spondylitis who received IFX or ADA and found that young age, shorter disease duration, and improved baseline functional status predicted response to anti-TNF-α therapy.
In our study, we have shown that 41% of patients receiving ADA for treatment of CD require dose escalation. This figure is higher than that observed in the CHARM trial (27%) and also in two retrospective analyses of ADA for the treatment of CD in pediatric populations (≈25%).14, 23, 24 Potential reasons for dose escalation include more severe disease in our referral center population, practice patterns at our center that differ from others, different patient expectations among those who seek care at a major IBD center, and a perhaps a higher incidence of antibodies against ADA (for which a commercial test is not yet available). Since our center is widely regarded as a “center of excellence” in the care of IBD, there may be less insurer “push back” against our requests for higher dosing, or perhaps just a difference geographically in the insurers' willingness to accept higher dosing regimens.
In our population, a family history of IBD was a significant predictor of the need for dose escalation. To our knowledge, this finding is the only reported predictor of the need for dose escalation among adult patients with CD. One possibility is that patients with a family history of IBD may harbor variant TNF-α alleles that impair neutralization by ADA or have higher levels of TNF-α and require higher doses to achieve the clinical response observed in patients without a family history. Polymorphisms in TNF-α have previously been identified that are associated with steroid-dependent and fistulizing disease.25 However, prior anti-TNF therapy was not a predictor of either dose escalation or time to dose escalation in this study, suggesting that another familial mechanism may be responsible.
Our IBD cohort is similar in many ways to others that have been studied previously. The breakdown of disease location is consistent with prior epidemiologic data regarding the natural history of CD.26 With regard to complicating features of CD, 43% of all subjects in our study had fistulizing disease, an incidence similar to that reported in Olmstead County (35%).27 Furthermore, almost two-thirds of patients in our study required surgery. This figure, while slightly higher than other populations with CD (41%–57%), underscores the complicated nature of our cohort's CD.28
The data from this study also differ from some other published experiences with ADA. In our study, 52% of participants achieved luminal remission without dose escalation and 90% of participants achieved clinical response. These rates are higher than those found in both the initial prospective studies that led to FDA approval for ADA as well as more recently reported experiences at tertiary care centers.9, 11, 12, 29 This is possibly attributable to variation in the clinical definitions of remission and response as determined by the four individual physicians involved in this study. Recall bias might have also influenced the results, as some information was not recorded in the patient record and was ascertained during the data collection process by approaching the attending physician or IBD nurse specialist. We did not utilize the Crohn's Disease Activity Index (CDAI), a validated measure of disease activity utilized in formal clinical trials, but not used in clinical practice. Our clinical population also had a large percentage who had previously been treated with IFX (69%), responded to the anti-TNF drug, and then either lost response, had an adverse reaction against the drug, or had a long hiatus between treatments. As a result, these particular patients were preselected as responders to anti-TNF therapy, which would also explain a high response rate to another anti-TNF agent such as ADA.
Our remission and response rates are also higher than those published recently by Swaminath et al30 in a retrospective analysis of 48 patients (mainly CD) treated with ADA. In that analysis, one patient achieved remission and 21/48 (43.8%) achieved clinical improvement. Of note, 88% of patients had received previous anti-TNF-α therapy, compared to 69% of participants in our study. While previous exposure to anti-TNF may select patients more likely to respond as described above, alternatively in some patients it might represent an especially difficult to treat group of patients who have a more severe phenotype or may have “rerouted” their immune system to non-TNF-dependent pathways. This has been seen in the clinical trials with ADA, certolizumab, and natalizumab, which have all shown subdued clinical response and remission rates in previous IFX responders.11, 31, 32
There are many other factors that might explain differences in response rates between studies, including patient demographics, compliance, physician experience in treating IBD, and others. Typically the patient population at a tertiary care center such as the University of Chicago has baseline disease that is more severe than other populations. In fact, the average disease duration in this study was almost 19 years. Many of the subjects received prior anti-TNF agents or surgery as part of their treatment program. The severity of disease seen in this study might result in overrepresentation of patients who might be refractory to initial dosing of therapy or other anti-TNF-α agents.
In conclusion, ADA is an effective therapy for the induction and maintenance of response and remission in patients with moderate to severe CD. In our tertiary care setting, greater than 4 of 10 patients require dose escalation above the standard 40 mg every 14 day maintenance regimen. Patients, caregivers, and payers should anticipate dose escalation and plan accordingly. Predictors of dose escalation and of earlier time to dose escalation point to those patients with a family history of CD, smokers, male gender, and colonic CD. Prospective studies are needed to determine whether patients with these high-risk characteristics should be reassessed sooner (i.e., by endoscopic or radiographic means) or even receive higher dosed maintenance therapy (i.e., 40 mg weekly or 80 mg every 2 weeks) to achieve better outcomes.
Disclosures: Drs. Cohen, Hanauer, and Rubin have all served in the past as consultants for Centocor, Inc. (now called Centocor Ortho Biotech Inc.) and for Abbott Laboratories. Drs. Cohen, Harrell, Hanauer, and Rubin have all served as investigators in clinical trials sponsored by Centocor, Inc. and in clinical trials sponsored by Abbott Laboratories. No funding was received by any company for the conduct of this current research.
- 18Factors predictive of response to cyclosporin treatment for severe, steroid-resistant ulcerative colitis. Am J Gastroenterol. 2000; 95: 2000–2008., , , et al.Direct Link: