- Email: [email protected]
C-Reactive Protein: Anti-Placebo or Predictor of Response
1114
EDITORIALS
GASTROENTEROLOGY Vol. 129, No. 3
C-Reactive Protein: Anti-Placebo or Predictor of Response See article on page 807.
he last 2 decades have witnessed an enormous evolution in our understanding of the biology of inflammation. This led to the development of new medications designed specifically to target one or a few components of the inflammatory pathway. As a result, the number of clinical trials for novel therapies has increased at an exponential rate.1 The placebo-controlled randomized clinical trial is the gold standard for proving efficacy. Unfortunately, such trials are expensive and time consuming, in part due to sample size requirements. Estimates of sample size requirements are largely driven by 3 factors, statistical power (the likelihood of detecting a difference if such a difference truly exists), the magnitude of difference in the rate of outcomes that the investigators hypothesize, and the outcome rate in the control arm. For example, assuming 80% power and a 1:1 ratio of patients treated with active drug or placebo, total sample size requirements range from 76 patients to detect a difference of 40% vs. 10% (absolute difference 30%), 88 patients to detect a difference of 50% vs. 20% (absolute difference 30%), and 182 patients to detect a difference of 40% vs. 20% (absolute difference 20%). Thus, one can reduce sample size requirements by keeping placebo-response rates low and the difference in response rates between arms large. In a previous meta-analysis, we identified that study duration, the number of study visits, and the severity of disease at the time of enrollment are each important predictors of the remission rate among patients with Crohn’s disease who receive placebo therapy. Most of the studies included in our meta-analysis either had not measured or did not report results stratified by C-reactive protein (CRP) levels. However, several studies suggest that CRP levels may be an important factor influencing remission and response rates in the placebo arm of clinical trials. Recently, Will et al2 performed a pooled analysis of response to placebo therapy using primary data from 13 clinical trials. In both acute disease and maintenance trials, mean CRP levels at randomization were lower in placebo responders than nonresponders. In this issue of GASTROENTEROLOGY, Schreiber et al3 report the results of a randomized, placebo-controlled trial of certolizumab pegol (CDP870), a PEGylated Fab’
T
fragment of humanized anti-TNF␣ monoclonal antibody, for active Crohn’s disease. The trial was designed to enroll 260 patients into 4 arms (65 patients per arm) to have 83% power to detect a 23% difference in treatment groups if the placebo-response rate was 12%. Although the certolizumab patients fared significantly better than the placebo-treated patients at numerous observation points, at week 12, the primary specified endpoint, the difference between any of the 3 doses of certolizumab and placebo was not statistically significant. Interestingly, the projected response rate in the active treatment arm at week 12 (12% ⫹ 23% ⫽ 35%) was very close to that observed in the trial (44.4%, 36.1%, and 36.5% in the 400, 200, and 100-mg groups respectively). What was not anticipated when the trial was designed was a placebo-response rate of 35.6% at week 12. In a post hoc analysis, the investigators note that in patients with baseline CRP concentration above 10 mg/L, the highest dose of certolizumab was superior to placebo at all time points. In contrast, among patients with CRP concentrations below 10 mg/L, the response rate among placebo-treated patients was slightly higher than among those in the active treatment arms (46.7% placebo vs. 38.1%, 38.6%, and 37.5% for the active treatment arms). In an additional post hoc analysis, the investigators document a strong correlation between baseline CRP levels and the placebo-response rate. In contrast, there was almost no difference in the response rates among the active treatment arms according to the CRP level at baseline. These data were only shown for patients with a CRP level of 5 mg/L or greater. This pattern of missing the primary endpoint despite other evidence that a drug is likely effective appears to be increasingly common. In recent years, several Crohn’s disease trials have failed to reach their pre-stated primary endpoint despite convincing evidence that the drug is likely effective. In a randomized, placebo-controlled trial of CDP571, a humanized anti-TNF␣ antibody, the primary outcome of clinical response at week 28 was not achieved, although a significant difference was observed at weeks 2 and 4.4 Likewise, among patients with a CRP concentration above 10 mg/L, response was more common in those receiving CDP571 compared with placebo both at week 2 and week 28.4 In a study of 248 patients, natalizumab was not significantly better than placebo for induction of remission after 6 weeks of therapy, but was significantly better than placebo at 4 weeks and 8
September 2005
weeks.5 In a larger randomized, placebo-controlled trial of natalizumab for active Crohn’s disease, the primary endpoint (clinical response at week 10) was again not significant; however, subgroup analysis demonstrated that among patients who had an elevated CRP level at baseline, the primary outcome was achieved significantly more often in patients treated with natalizumab than those receiving placebo at 10 weeks and multiple other time points.6 One of the common themes among these trials is that the drug appears superior to placebo in the subgroup of patients with high CRP concentrations, but not in those with low CRP levels. There are several potential explanations for this phenomenon. Some patients with low CRP likely do not have active Crohn’s disease despite an elevated Crohn’s Disease Activity Index (CDAI) score. Although the CDAI has become the standard outcome measure for Crohn’s disease clinical trials, it is far from perfect. Patients with diarrhea and abdominal symptoms from causes other than Crohn’s disease, particularly concomitant irritable bowel syndrome (IBS), can achieve a CDAI score sufficient for entry into most clinical trials. While there is little reason to think that anti-inflammatory therapies would have a significant effect on these patients, spontaneous waxing and waning of symptoms is common to IBS and would result in a high placebo response rate.7,8 Similar effects would be expected with patients who had a concomitant infection. Patients with strictures, bile salt–induced diarrhea, or diarrhea secondary to reduced bowel surface area may also have high CDAI scores and may not be responsive to anti-inflammatory therapies. Whether inclusion of these patients would increase or decrease the placebo response rate is less clear, although one might expect that these patients would be less likely to show spontaneous improvement, and therefore should not contribute to a high placebo response rate. In many of these trials, more than half of the patients had low CRP concentrations, typically below 10 mg/L.3,4 It seems implausible to expect that half of the patients enrolled in these trials had elevated CDAI scores on the basis of concomitant IBS or infection rather than active Crohn’s disease. As such, while the high placebo response rate among patients with a low CRP may be partially explained by inclusion of people with concomitant IBS, other factors must have contributed. Inclusion of patients with mild to moderate Crohn’s disease and with low CRP levels is a viable possibility.9,10 Solem et al11 recently reported that severe inflammation on biopsy, but not mild or moderate disease, was associated with an elevated CRP concentration. This population with mild inflammation may have sufficient symptoms to meet
EDITORIALS
1115
study entry criteria and may be more likely to experience spontaneous improvement in their disease. Given the reproducibility of the fraction of patients with high and low CRP levels in these multiple trials and the high placebo response rates, further exploration of this hypothesis is warranted. How then can we use this information to improve the conduct of clinical trials? One option is to limit enrollment to patients with elevated CRP. While this would likely decrease the required sample size, it would increase the number of patients who need to be screened for entry into the study. Perhaps more importantly, it would not provide information on how the drug performs in patients without an elevated CRP concentration. A second method to improve the efficiency of clinical trials is to select the shortest time point that makes biological sense as the primary outcome measure. This strategy will minimize the effect of the cyclical nature of Crohn’s disease. We have previously shown that placebo remission rates increase with time,1 and this was born out again in these recent clinical trials.3–5 In the case of CD571 and certolizumab, both drugs were significantly more effective than placebo at the first interim visit.3,4 In one study, natalizumab was also superior to placebo at week 4, although not at week 2 or at week 6, the primary endpoint.5 While this strategy could improve the efficiency at testing efficacy, it would not obviate the need for long-term studies to determine durability of the effect and safety. Ultimately, these data may also be able to help us improve our treatment of patients in routine clinical care. Identifying strong predictors of clinical response should be a priority. With increasing development of expensive, and potentially toxic, therapies, we need to optimize the benefit to risk profile of our therapies. Clinical trials are helpful to identify which therapies are efficacious and provide some data on who is most likely to respond. However, generalizability of clinical trials data to general practice is always a question. Likewise, because of strict entry criteria and small sample sizes, clinical trials play a limited role in identifying the risks of therapy. Post-approval observational studies can help answer these questions. For example, one such study identified CRP concentrations as an independent predictor of response to infliximab.12 Similar results were observed in the high-dose arm of the certolizumab study.3 Ultimately, measuring CRP and other biomarkers should allow us to tailor our therapy recommendations specifically to our patients, thereby optimizing the benefit to risk ratio. In the short term, given that patients with signs or symptoms of active disease and a low CRP concentration
1116
EDITORIALS
may be more likely to spontaneously improve, one might demand further evidence of active inflammation, such as visualization of active mucosal disease, before embarking on a potentially toxic therapy. In contrast, for those patients with active symptoms and an elevated CRP level, the low likelihood of spontaneous improvement shifts the benefit to risk ratio further in favor of our currently available therapies. Such data could be used to counsel patients who are uncertain about initiating a new medication. At the end of the day, there is something to be learned from nearly every clinical study. The important work of Schreiber et al3 should not be overlooked for failure to achieve their primary outcome. Rather, these results can be used to guide future studies of certolizumab and other medications. Furthermore, their data on CRP and clinical response rates in the placebo arm may be of value in counseling our patients considering a new medical therapy. Science and medicine move slowly. Seventy-five years after its original description in patients with pneumonia,13 CRP may have found a new home in the management of Crohn’s disease. JAMES D. LEWIS Department of Medicine Department of Biostatistics and Epidemiology Center for Clinical Epidemiology and Biostatistics University of Pennsylvania Philadelphia, Pennsylvania
GASTROENTEROLOGY Vol. 129, No. 3
4.
5.
6.
7.
8.
9.
10.
11.
12.
References 1. Su C, Lichtenstein GR, Krok K, Brensinger CM, Lewis JD. A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn’s disease. Gastroenterology 2004; 126:1257–1269. 2. Will M, Nikolaus S, Freitag S, Arpe N, Krawczak M, Schreiber S. Placebo response in the therapy of Crohn’s disease: a comprehensive analysis of primary data from 733 patients from 13 randomized controlled trials. Gastroenterology 2005;128(Suppl 2):A-48. 3. Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kann MA, Boivin M, Bernstein CN, Staun M, Thomsen O, Innes A. A randomized, placebo-controlled trial of Certolizumab pegol
13.
(CDP870) for treatment of Crohn’s disease. Gastroenterology 2005;129:807– 818. Sandborn WJ, Feagan BG, Radford-Smith G, Kovacs A, Enns R, Innes A, Patel J. CDP571, a humanised monoclonal antibody to tumour necrosis factor alpha, for moderate to severe Crohn’s disease: a randomised, double blind, placebo controlled trial. Gut 2004;53:1485–1493. Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, Vyhnalek P, Zadorova Z, Palmer T, Donoghue S, Natalizumab Pan-European Study G. Natalizumab for active Crohn’s disease. N Engl J Med 2003;348:24 –32. Rutgeerts P, Colombel JF, Enns J. Subanalysis from a phase 3 study on the evaluation of natalizumab in active Crohn’s disease. Gut 2003;52(Suppl):A239. Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet 2000;355:1035–1040. Camilleri M, Chey WY, Mayer EA, Northcutt AR, Heath A, Dukes GE, McSorley D, Mangel AM. A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch Intern Med 2001;161:1733–1740. Fagan EA, Dyck RF, Maton PN, Hodgson HJ, Chadwick VS, Petrie A, Pepys MB. Serum levels of C-reactive protein in Crohn’s disease and ulcerative colitis. Eur J Clin Invest 1982;12:351–359. Chambers RE, Stross P, Barry RE, Whicher JT. Serum amyloid A protein compared with C-reactive protein, alpha 1-antichymotrypsin and alpha 1-acid glycoprotein as a monitor of inflammatory bowel disease. Eur J Clin Invest 1987;17:460 – 467. Solem CA, Loftus EV, Tremaine WJ, Harmsen S, Zinsmeister AR, Sandborn WJ. Correlation of C-reactive protein (CRP) with clinical, radiographic, and endoscopic activity in inflammatory bowel disease. Gastroenterology 2004;126(Suppl 2):A-477. Louis E, Vermeire S, Rutgeerts P, De Vos M, Van Gossum A, Pescatore P, Fiasse R, Pelckmans P, Reynaert H, D’Haens G, Malaise M, Belaiche J. A positive response to infliximab in Crohn disease: association with a higher systemic inflammation before treatment but not with -308 TNF gene polymorphism. Scand J Gastroenterol 2002;37:818 – 824. Tillet W, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of the Pneumococcus. J Exp Med 1930;52:561–571.
Address requests for reprints to: James D. Lewis, MD, MSCE, 720 Blockley Hall, 423 Guardian Drive, Philadelphia, Pennsylvania 19104. e-mail: [email protected]; fax: (215) 573-5325. © 2005 by the American Gastroenterological Association 0016-5085/05/$30.00 doi:10.1053/j.gastro.2005.07.041
EDITORIALS
GASTROENTEROLOGY Vol. 129, No. 3
C-Reactive Protein: Anti-Placebo or Predictor of Response See article on page 807.
he last 2 decades have witnessed an enormous evolution in our understanding of the biology of inflammation. This led to the development of new medications designed specifically to target one or a few components of the inflammatory pathway. As a result, the number of clinical trials for novel therapies has increased at an exponential rate.1 The placebo-controlled randomized clinical trial is the gold standard for proving efficacy. Unfortunately, such trials are expensive and time consuming, in part due to sample size requirements. Estimates of sample size requirements are largely driven by 3 factors, statistical power (the likelihood of detecting a difference if such a difference truly exists), the magnitude of difference in the rate of outcomes that the investigators hypothesize, and the outcome rate in the control arm. For example, assuming 80% power and a 1:1 ratio of patients treated with active drug or placebo, total sample size requirements range from 76 patients to detect a difference of 40% vs. 10% (absolute difference 30%), 88 patients to detect a difference of 50% vs. 20% (absolute difference 30%), and 182 patients to detect a difference of 40% vs. 20% (absolute difference 20%). Thus, one can reduce sample size requirements by keeping placebo-response rates low and the difference in response rates between arms large. In a previous meta-analysis, we identified that study duration, the number of study visits, and the severity of disease at the time of enrollment are each important predictors of the remission rate among patients with Crohn’s disease who receive placebo therapy. Most of the studies included in our meta-analysis either had not measured or did not report results stratified by C-reactive protein (CRP) levels. However, several studies suggest that CRP levels may be an important factor influencing remission and response rates in the placebo arm of clinical trials. Recently, Will et al2 performed a pooled analysis of response to placebo therapy using primary data from 13 clinical trials. In both acute disease and maintenance trials, mean CRP levels at randomization were lower in placebo responders than nonresponders. In this issue of GASTROENTEROLOGY, Schreiber et al3 report the results of a randomized, placebo-controlled trial of certolizumab pegol (CDP870), a PEGylated Fab’
T
fragment of humanized anti-TNF␣ monoclonal antibody, for active Crohn’s disease. The trial was designed to enroll 260 patients into 4 arms (65 patients per arm) to have 83% power to detect a 23% difference in treatment groups if the placebo-response rate was 12%. Although the certolizumab patients fared significantly better than the placebo-treated patients at numerous observation points, at week 12, the primary specified endpoint, the difference between any of the 3 doses of certolizumab and placebo was not statistically significant. Interestingly, the projected response rate in the active treatment arm at week 12 (12% ⫹ 23% ⫽ 35%) was very close to that observed in the trial (44.4%, 36.1%, and 36.5% in the 400, 200, and 100-mg groups respectively). What was not anticipated when the trial was designed was a placebo-response rate of 35.6% at week 12. In a post hoc analysis, the investigators note that in patients with baseline CRP concentration above 10 mg/L, the highest dose of certolizumab was superior to placebo at all time points. In contrast, among patients with CRP concentrations below 10 mg/L, the response rate among placebo-treated patients was slightly higher than among those in the active treatment arms (46.7% placebo vs. 38.1%, 38.6%, and 37.5% for the active treatment arms). In an additional post hoc analysis, the investigators document a strong correlation between baseline CRP levels and the placebo-response rate. In contrast, there was almost no difference in the response rates among the active treatment arms according to the CRP level at baseline. These data were only shown for patients with a CRP level of 5 mg/L or greater. This pattern of missing the primary endpoint despite other evidence that a drug is likely effective appears to be increasingly common. In recent years, several Crohn’s disease trials have failed to reach their pre-stated primary endpoint despite convincing evidence that the drug is likely effective. In a randomized, placebo-controlled trial of CDP571, a humanized anti-TNF␣ antibody, the primary outcome of clinical response at week 28 was not achieved, although a significant difference was observed at weeks 2 and 4.4 Likewise, among patients with a CRP concentration above 10 mg/L, response was more common in those receiving CDP571 compared with placebo both at week 2 and week 28.4 In a study of 248 patients, natalizumab was not significantly better than placebo for induction of remission after 6 weeks of therapy, but was significantly better than placebo at 4 weeks and 8
September 2005
weeks.5 In a larger randomized, placebo-controlled trial of natalizumab for active Crohn’s disease, the primary endpoint (clinical response at week 10) was again not significant; however, subgroup analysis demonstrated that among patients who had an elevated CRP level at baseline, the primary outcome was achieved significantly more often in patients treated with natalizumab than those receiving placebo at 10 weeks and multiple other time points.6 One of the common themes among these trials is that the drug appears superior to placebo in the subgroup of patients with high CRP concentrations, but not in those with low CRP levels. There are several potential explanations for this phenomenon. Some patients with low CRP likely do not have active Crohn’s disease despite an elevated Crohn’s Disease Activity Index (CDAI) score. Although the CDAI has become the standard outcome measure for Crohn’s disease clinical trials, it is far from perfect. Patients with diarrhea and abdominal symptoms from causes other than Crohn’s disease, particularly concomitant irritable bowel syndrome (IBS), can achieve a CDAI score sufficient for entry into most clinical trials. While there is little reason to think that anti-inflammatory therapies would have a significant effect on these patients, spontaneous waxing and waning of symptoms is common to IBS and would result in a high placebo response rate.7,8 Similar effects would be expected with patients who had a concomitant infection. Patients with strictures, bile salt–induced diarrhea, or diarrhea secondary to reduced bowel surface area may also have high CDAI scores and may not be responsive to anti-inflammatory therapies. Whether inclusion of these patients would increase or decrease the placebo response rate is less clear, although one might expect that these patients would be less likely to show spontaneous improvement, and therefore should not contribute to a high placebo response rate. In many of these trials, more than half of the patients had low CRP concentrations, typically below 10 mg/L.3,4 It seems implausible to expect that half of the patients enrolled in these trials had elevated CDAI scores on the basis of concomitant IBS or infection rather than active Crohn’s disease. As such, while the high placebo response rate among patients with a low CRP may be partially explained by inclusion of people with concomitant IBS, other factors must have contributed. Inclusion of patients with mild to moderate Crohn’s disease and with low CRP levels is a viable possibility.9,10 Solem et al11 recently reported that severe inflammation on biopsy, but not mild or moderate disease, was associated with an elevated CRP concentration. This population with mild inflammation may have sufficient symptoms to meet
EDITORIALS
1115
study entry criteria and may be more likely to experience spontaneous improvement in their disease. Given the reproducibility of the fraction of patients with high and low CRP levels in these multiple trials and the high placebo response rates, further exploration of this hypothesis is warranted. How then can we use this information to improve the conduct of clinical trials? One option is to limit enrollment to patients with elevated CRP. While this would likely decrease the required sample size, it would increase the number of patients who need to be screened for entry into the study. Perhaps more importantly, it would not provide information on how the drug performs in patients without an elevated CRP concentration. A second method to improve the efficiency of clinical trials is to select the shortest time point that makes biological sense as the primary outcome measure. This strategy will minimize the effect of the cyclical nature of Crohn’s disease. We have previously shown that placebo remission rates increase with time,1 and this was born out again in these recent clinical trials.3–5 In the case of CD571 and certolizumab, both drugs were significantly more effective than placebo at the first interim visit.3,4 In one study, natalizumab was also superior to placebo at week 4, although not at week 2 or at week 6, the primary endpoint.5 While this strategy could improve the efficiency at testing efficacy, it would not obviate the need for long-term studies to determine durability of the effect and safety. Ultimately, these data may also be able to help us improve our treatment of patients in routine clinical care. Identifying strong predictors of clinical response should be a priority. With increasing development of expensive, and potentially toxic, therapies, we need to optimize the benefit to risk profile of our therapies. Clinical trials are helpful to identify which therapies are efficacious and provide some data on who is most likely to respond. However, generalizability of clinical trials data to general practice is always a question. Likewise, because of strict entry criteria and small sample sizes, clinical trials play a limited role in identifying the risks of therapy. Post-approval observational studies can help answer these questions. For example, one such study identified CRP concentrations as an independent predictor of response to infliximab.12 Similar results were observed in the high-dose arm of the certolizumab study.3 Ultimately, measuring CRP and other biomarkers should allow us to tailor our therapy recommendations specifically to our patients, thereby optimizing the benefit to risk ratio. In the short term, given that patients with signs or symptoms of active disease and a low CRP concentration
1116
EDITORIALS
may be more likely to spontaneously improve, one might demand further evidence of active inflammation, such as visualization of active mucosal disease, before embarking on a potentially toxic therapy. In contrast, for those patients with active symptoms and an elevated CRP level, the low likelihood of spontaneous improvement shifts the benefit to risk ratio further in favor of our currently available therapies. Such data could be used to counsel patients who are uncertain about initiating a new medication. At the end of the day, there is something to be learned from nearly every clinical study. The important work of Schreiber et al3 should not be overlooked for failure to achieve their primary outcome. Rather, these results can be used to guide future studies of certolizumab and other medications. Furthermore, their data on CRP and clinical response rates in the placebo arm may be of value in counseling our patients considering a new medical therapy. Science and medicine move slowly. Seventy-five years after its original description in patients with pneumonia,13 CRP may have found a new home in the management of Crohn’s disease. JAMES D. LEWIS Department of Medicine Department of Biostatistics and Epidemiology Center for Clinical Epidemiology and Biostatistics University of Pennsylvania Philadelphia, Pennsylvania
GASTROENTEROLOGY Vol. 129, No. 3
4.
5.
6.
7.
8.
9.
10.
11.
12.
References 1. Su C, Lichtenstein GR, Krok K, Brensinger CM, Lewis JD. A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn’s disease. Gastroenterology 2004; 126:1257–1269. 2. Will M, Nikolaus S, Freitag S, Arpe N, Krawczak M, Schreiber S. Placebo response in the therapy of Crohn’s disease: a comprehensive analysis of primary data from 733 patients from 13 randomized controlled trials. Gastroenterology 2005;128(Suppl 2):A-48. 3. Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kann MA, Boivin M, Bernstein CN, Staun M, Thomsen O, Innes A. A randomized, placebo-controlled trial of Certolizumab pegol
13.
(CDP870) for treatment of Crohn’s disease. Gastroenterology 2005;129:807– 818. Sandborn WJ, Feagan BG, Radford-Smith G, Kovacs A, Enns R, Innes A, Patel J. CDP571, a humanised monoclonal antibody to tumour necrosis factor alpha, for moderate to severe Crohn’s disease: a randomised, double blind, placebo controlled trial. Gut 2004;53:1485–1493. Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, Vyhnalek P, Zadorova Z, Palmer T, Donoghue S, Natalizumab Pan-European Study G. Natalizumab for active Crohn’s disease. N Engl J Med 2003;348:24 –32. Rutgeerts P, Colombel JF, Enns J. Subanalysis from a phase 3 study on the evaluation of natalizumab in active Crohn’s disease. Gut 2003;52(Suppl):A239. Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet 2000;355:1035–1040. Camilleri M, Chey WY, Mayer EA, Northcutt AR, Heath A, Dukes GE, McSorley D, Mangel AM. A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch Intern Med 2001;161:1733–1740. Fagan EA, Dyck RF, Maton PN, Hodgson HJ, Chadwick VS, Petrie A, Pepys MB. Serum levels of C-reactive protein in Crohn’s disease and ulcerative colitis. Eur J Clin Invest 1982;12:351–359. Chambers RE, Stross P, Barry RE, Whicher JT. Serum amyloid A protein compared with C-reactive protein, alpha 1-antichymotrypsin and alpha 1-acid glycoprotein as a monitor of inflammatory bowel disease. Eur J Clin Invest 1987;17:460 – 467. Solem CA, Loftus EV, Tremaine WJ, Harmsen S, Zinsmeister AR, Sandborn WJ. Correlation of C-reactive protein (CRP) with clinical, radiographic, and endoscopic activity in inflammatory bowel disease. Gastroenterology 2004;126(Suppl 2):A-477. Louis E, Vermeire S, Rutgeerts P, De Vos M, Van Gossum A, Pescatore P, Fiasse R, Pelckmans P, Reynaert H, D’Haens G, Malaise M, Belaiche J. A positive response to infliximab in Crohn disease: association with a higher systemic inflammation before treatment but not with -308 TNF gene polymorphism. Scand J Gastroenterol 2002;37:818 – 824. Tillet W, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of the Pneumococcus. J Exp Med 1930;52:561–571.
Address requests for reprints to: James D. Lewis, MD, MSCE, 720 Blockley Hall, 423 Guardian Drive, Philadelphia, Pennsylvania 19104. e-mail: [email protected]; fax: (215) 573-5325. © 2005 by the American Gastroenterological Association 0016-5085/05/$30.00 doi:10.1053/j.gastro.2005.07.041