The use of Adalimumab as effective maintenance treatment for the response and remission in patients with moderate to severe Crohn’s disease, with optimal Crohn’s Disease Activity Index (CDAI) points decrease as an endpoint.
Table of Contents
Crohn’s disease (CD) is a chronic incurable inflammatory bowel disease of unknown aetiology, considered to be an autoimmune disorder, affecting both the mucosal and transmural layers of the gastrointestinal tract bowel wall, in the form of fissures, fibrosis, abscesses and fistulas from the mouth through to the anus (Lennard-Jones, 1989; Mocko, Kawalec, & Pilc, 2016; Thomas et al., 2014; Triester et al., 2006). The pathogenesis of CD is a combination of genetic susceptibility, luminal microbial pathogens, immune response and environmental triggers (Sartor, 2006). Mutations in Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a gene that stimulates immune reactions to bacterial molecules, has a strong association consistent with CD (Sartor, 2006; Watanabe, Kitani, Murray, & Strober, 2004), but with different theories as to the specificity of how NOD2 increases susceptibility of CD posited.
Incidence rates and prevalence for CD suggests a gradient from North to South globally (Baumgart & Carding, 2007), and effects Caucasian and Jewish individuals more than any other ethnicity (Hanauer, 2006). Loftus (2004) and Economou, Zambeli, and Michopoulos (2009) indicate that CD affects 26-200 per 100,000 in European countries, with less clinical presentations in non-European countries, and interestingly Canterbury in New Zealand has one of the highest rates of diagnosis of CD worldwide estimated at 16.5/105 in 2004, with data suggesting the incidence rate of CD is lower in Maori and Pacific Islanders (Economou et al., 2009; Gearry et al., 2006). Women are slightly more susceptible to developing CD, with a 51-49% diagnosis respectively (Hovde & Moum, 2012); and Liu and Anderson (2014) identify a familiar component to CD presentations suggesting a genetic link.
The medical management of CD symptoms include steroids, immunosuppressant’s and Non-Steroidal Anti-inflammatory Drugs (NSAIDs) (Gearry & Day, 2008); and in more recent years’ biological therapies, such as Tumour Necrosis Factor (TNF) inhibitors, have revolutionised the management of CD by blocking the signalling pathways of TNF, which promote the inflammatory response in CD (Rutgeerts, Vermeire, & Van Assche, 2009).
This assignment discusses the pathogenesis of Crohn’s Disease, in addition three Randomized Controlled Trials (RCTs) are presented which provides evidence that the use of Adalimumab is an effective maintenance treatment for the response and remission of CD. The findings from these studies will be reviewed in the context of managing patients with moderate to severe CD using the Crohn’s Disease Activity Index (CDAI) (See appendix A).
The most common hypothesis for CD is a pronounced increase of T helper type 1 (Th1) cells in an inappropriate response to commensal bacteria, due to environmental triggers (Abraham & Cho, 2009; Mow et al., 2004; Sartor, 2006; Watanabe et al., 2004). Th1 secretes TNF a cell signalling protein involved in the pro-inflammatory cytokine cascade and dysregulation of TNF is implicated in CD, thought to be due to inflammatory responses not being down-regulated after exposure to a pathogen (Colombel et al., 2007; Hanauer, 2006; Parameswaran & Patial, 2010).
Aberrant TNF over excite the inflammatory response resulting in microscopic foci developing in the superficial mucosal layer of the bowel (Abraham & Cho, 2009; Mow et al., 2004). Neutrophil infiltration results in further inflammatory responses with abscesses being formed in the submucosal layer due to the proliferation of smooth muscle from the muscularis, causing atrophy to the mucosal wall (Sartor, 2006; Sheehan, Warren, Gear, & Shepherd, 1992). Chronic damage to the bowel mucosa is evident in the form of thickening of the bowel wall and narrowing of the lumen, which if left untreated can cause a bowel obstruction (Abraham & Cho, 2009). As CD progresses, this is further complicated by deep ulcers which can penetrate the serosal layer and fistulate into adjacent organs such as the bladder or vagina. The inflammatory prostaglandins actioned by cyclooxygenase (COX) isoenzymes can also cause adhesions to form around the initial focal area leading to ulceration of the superficial mucosa, and invasion of the deep mucosal layers continuing through the entire bowel wall into the mesentery and regional lymph nodes (Abraham & Cho, 2009; Sartor, 2006).
The diagnosis of CD includes a combination of histological, endoscopic, clinical, radiological and biochemical tests (Fireman et al., 2003; Triester et al., 2006), with a CDAI score generated. Gasche, Lomer, Cavill, and Weiss (2004) anticipate that one third of CD sufferers will develop an iron deficiency anaemia due to intestinal bleeding. Canavan, Abrams, and Mayberry (2006) discuss a 2.9% increased risk of colorectal cancer for CD patients over the general population, with no clear evidence to suggest the reason for this; however, Freeman (2008) intimated that the differential diagnosis for colorectal cancer could be confused with CD symptoms and therefore detected late. Clinical presentations of CD include diarrhoea, abdominal pain and or bleeding and severe weight loss due to a disturbance in normal gut motility and digestive processes.(Podolsky 1991; Su, Gupta, Day, & Gearry, 2016).. According to Cosnes, Gower-Rousseau, Seksik, and Cortot (2011) CD patients have a slighter higher chance of mortality than the general population, however this could be associated with higher risk of death due to postoperative complications, malnutrition and colorectal cancer.
Risk factors that could exacerbate or effect presentation of CD such as environment, lifestyle and diet have been discussed, with several studies demonstrating the effect of diet on CD symptoms (Laing, Han, & Ferguson, 2013; Loftus, 2004; Ng et al., 2013; Triggs et al., 2010). Timmer, Sutherland, and Martin (1998) attributed smoking and oral contraception with recurrent attacks or flare up of CD symptoms; and Hovde and Moum (2012), linked a rise in reported new diagnosis of CD on people who had had an appendectomy, but this appears questionable and required further evidence to support the claim.
There is currently no cure for CD, and symptom management consists of pharmacological management, diet modification and surgery, when the former two fail (Liu & Anderson, 2014; Sandborn, Rutgeerts, Enns, & et al., 2007). Reduction in CDAI scores translates into reduced CD hospitalisation (Thomas et al., 2014), and better Quality of Life (QOL) (Thia et al., 2008). In recent years’ biologic agents, produced from living biological sources and genetically engineered, such as Adalimumab have been considered for the treatment of CD. The plausible biological rationale being that adalimumab is a fully human immunoglobulin G1 monoclonal antibody that binds with high affinity and specificity to TNF with the aim of blocking TNF receptors, therefore inhibiting the inflammatory processes allowing maintenance and clinical remission of CD, reduced CDAI score and improved QOL (Bongartz et al., 2006; Colombel et al., 2007; Rutgeerts et al., 2009; Sandborn, Hanauer, et al., 2007).
The risk-benefit effect of anti-TNF medications in patients treated with adalimumab for rheumatoid arthritis (RA) demonstrated a risk of infections and malignancy diagnoses (Peyrin–Biroulet et al., 2008), although the link with concomitant medication associated with RA has to be taken into consideration. The Number Needed to Harm was posited at 154 (95% CI, 39-125) within a 12 month period (Bongartz et al., 2006), and according to Peyrin–Biroulet et al. (2008) these results should not be directly transferred to CD, due to the different pathogenesis of the two inflammatory diseases. According to New Zealand Formulary (2017), adalimumab is contraindicated in patients with moderate to severe heart failure, and considerations must include the patient’s defence system being compromised, allowing opportunistic infections to increase.
RCTs and Table
All three studies had the same criteria for the diagnosis of CD, as well as the inclusion criteria. The Intention to treat (ITT) population included patients aged between 18 and 75 years, with moderate to severe active Crohn’s disease at baseline, as defined by the Crohn’s Disease Activity Index (CDAI), with radiologic or endoscopic evidence confirming diagnosis of Crohn’s disease for at least four months. Optimal CDAI response is a decrease in CDAI score from baseline to either >70 points after two weeks, or a decrease in CDAI of >100 after four weeks.
Study 1 CLASSIC I Trial
Sandborn, Hanauer, et al. (2007) from the Mayo clinic performed a four week, multi-centre, randomised, double-blind, placebo-controlled trial, to evaluate the efficacy of adalimumab induction therapy for response and remission of CD in 299 patients
The ITT group were randomized to receive either adalimumab 40/20 mg, 80/40 mg, or 160/80 mg or placebo at weeks zero and two respectively. Using Pearson’s X2 test with a 0.05 2-sided significance level had 80% power to detect response rates for the two highest doses of adalimumab and placebo for induction of remission, based on assumptions of 45% and 20% induction of remission rate for both adalimumab groups and the placebo respectively, with the primary efficacy endpoint being remission at week 4 as defined by CDAI <150.
Exclusions included patients non-naïve to TNF antagonists, those who were on unstable concurrent therapy doses or who had been on antibiotics for other unrelated issues. Patients who had had recent bowel resections or other bowel related pathologies, pregnant or breast feeding women, those with abnormal ECG, liver function tests and creatinine, and those who had significant drug or alcohol addictions were also excluded.
The remission rates at week four in the adalimumab 40/20 mg (n=74/299), 80/40 mg (n=75/299), and 160/80 mg (n=75/299) groups were 18% (p=0.36), 24% (p= 0.06), and 36% respectively (p=0.001), and 12% in the placebo group. There was a linear dose response across all adalimumab treatment groups at week four demonstrating the endpoint of remission of CD.
Adverse events occurred on 1% (n=1/74) and (n=1/75) for both the adalimumab 40/20 mg, and 80/40 mg respectively, whilst none of the adalimumab 160/80 mg group reported any adverse events compared with 3% (n=2/74) in the placebo group.
Induction therapy with adalimumab at week zero and two is superior to placebo for inducing remission and response (70-point and 100-point response) in CD.
Study 2 GAIN Trial
Sandborn, Rutgeerts, et al. (2007) from the Mayo Clinic performed a four week, multicentre, randomised, double-blind, placebo-controlled trial, to determine whether adalimumab induces response and remissions more frequently than placebo, in 325 patients who are naïve to Infliximab.
The ITT group were assessed for two weeks prior to being randomly assigned to receive induction doses of adalimumab, 160 mg and 80 mg, at weeks 0 and 2, respectively, or placebo at the same time points. It was estimated that at least 300 patients would be required to achieve 80% power to detect absolute difference in clinical remission rates of 15%, with the primary efficacy endpoint being remission at week 4.
Exclusions included patients who previously had received, or who were nonresponsive to other TNF antagonists, those who were on unstable concurrent therapy doses or who had been on antibiotics for other unrelated issues. Patients who had had recent bowel resections or other bowel related pathologies, pregnant or breast feeding women, those with abnormal ECG, liver function tests and creatinine, and those who had significant drug or alcohol addictions were also excluded.
At week four, the comparison between the groups with regards to clinical remission was 21% (34/159) and 7% (12/166) respectively (P <0.001). The absolute difference in rates of remission between the two groups was 14.2 percentage points (95% CI, 6.7 – 21.6 percentage points). At week four, the rates of 70-point response and 100-point response were greater in the adalimumab group than in the placebo: 52% versus 34%; and 38% versus 25% respectively. The differences in 70-point response and 100-point response between the groups at week four were 17.8 percentage points (CI 7.3-28.4 percentage points), and 13.7 percentage points (CI, 3.7-23.7 percentage points) respectively.
Patients who received adalimumab were more likely to achieve remission (70-point and 100-point response) at four weeks, than those on placebo.
Study 3 CHARM Trial
Colombel et al. (2007) from France performed a 56-week multicentre, double blind, randomised, placebo-controlled trial, assessing long-term efficacy and safety of adalimumab in maintenance of response and clinical remission of CD in in 854 patients.
The ITT group entered two-weeks of screening where they received adalimumab 80 mg and 40 mg at week zero and two respectively; at week four, they were randomised to one of three treatment groups, adalimumab 40 mg every other week (eow) (n=260/778), 40mg weekly (n=257/778), or placebo (n=261/778). At weeks four and 12 patients experiencing >70 CDAI points, or had CDAI score >220 were switched to open-label treatment with 40 mg eow, increased to 40 mg weekly if non-response or flare up of CD occurred. It was estimated that 160 patients per group (n=480) would provide a statistical power of 87% at 0.05 -level to detect a 14% absolute difference in clinical remission rates between adalimumab and placebo groups, assuming a 14% and 28 % remission rate in the placebo arm and adalimumab arms at week 56 respectively. The primary endpoint was remission at week 56.
Exclusions included patients with recent bowel resections or other bowel related pathologies, those on total parental nutrition or who had a history of cancer, listeria, HIV, CNS disease, or untreated TB; those who were pregnant or breastfeeding, and those with poorly controlled medical conditions. Patients that received investigative chemical agents within 30 days, biologic agents within three months, antibiotics within three weeks, or had significant drug or alcohol addictions were also excluded.
A total of 59% (n=505) completed the 56-week study, with the rates of clinical remission among responders for placebo, 40mg eow, and 40 mg weekly being 17%, 40% and 47% at week 26 and 12%, 36% and 41% at week 56, respectively. The week 26 and 56 remission rates for both adalimumab groups were statistically higher than placebo, P <0.001.
This study demonstrated that adalimumab was effective for maintaining remission (70-point and 100-point response), in patients with moderate to severe CD, regardless of prior anti TNF exposure.
Table 1. Summary of randomised controlled trials that evaluated efficacy of Adalimumab on maintenance of response and remission in patients with moderate to severe Crohn’s disease as defined by CDAI <150 points.
|(Hanauer et al., 2006)
CLASSIC I Trial:
Randomized, double blind, placebo controlled study.
Efficacy of adalimumab induction therapy in patients with CD.
Follow up: 4 weeks
Remission after 4 weeks:
|Sandborn, Rutgeerts, et al. (2007)
Randomized, double blind, placebo-controlled trial.
Determine whether adalimumab induces remissions more frequently than placebo in patients with CD.
Remission after 4 weeks:
|Colombel et al. (2007)
Randomized, double blind, placebo controlled study.
Efficacy and safety of adalimumab in the maintenance of response and remission in patients with moderate to severe CD
Follow up: 56 weeks
Remission after 56 weeks:
Abbreviations: Ada, Adalimumab; eow, every other week; CDAI, Crohn’s Disease Activity Index.
The point estimate for all three studies described efficacy and safety of adalimumab in the induction and maintenance of response and remission of patients with moderate to severe CD, and according to Peyrin–Biroulet et al. (2008) the studies were considered to be of high quality with a Jadad score >3 points. All three studies failed to predict the Numbers needed to treat (NNT), however, Peyrin–Biroulet et al. (2008) meta-analysis, presented the NNT for the CHARM study as four, among the responders in the overall analysis which increased to nine, when both responders and non-responders to induction therapy were included; meaning nine people will need to be treated to avoid exacerbation of CD.
There was a clear dose-response effect as clinical remission was achieved in 31% (n=218/713) of all patients in the adalimumab arms of the three studies, compared with only 10% (n= 41/410) in the placebo groups. The results were statistically significant with the p-value being greater than 0.001, allowing a rejection of the null hypothesis, as there is no difference between the sample or placebo group. The confidence intervals were not provided in all the studies, but Sandborn, Rutgeerts, et al. (2007), presented a 14.2 percentage point margin of error in the rates of clinical remission of CD at the conclusion of the CHARM trial (95% CI, 6.7 – 21.6), demonstrating statistical significance, particularly as this was the 56 week follow up trial.
In overall analysis, adverse events were more common in the placebo groups 15.3% versus the adalimumab groups 8.2%, with the majority being injection site issues. Serious adverse events were observed less, but it would be interesting to see if these changed over time with regard to efficacy of TNF inhibitor and possible increased infection rates and cancer rates.
The CDAI was used to demonstrate efficacy in all three RCTs, due to the ability to record baseline disease activity and measure treatment effects during the trials. The quality of life (QOL) as defined by CDAI <150, (Rutgeerts et al., 2009) was maintained in patients receiving adalimumab in all three studies, whereas it rapidly declined in participants on placebo, demonstrating that continuous response to adalimumab correlates to improvements in the QOL.
Adalimumab is currently used for CD in New Zealand but only if the patient has a CDAI score greater than 300, and will only be continued if the CDAI score has been reduced by 100 points, or is less than 150 after four weeks of use (PHARMAC, 2017), which is in following with all three RCTs evaluations.
Crohn’s disease is an inflammatory disease of unknown aetiology of the gastrointestinal tract, associated with a mutant NOD2 gene, and aberrant TNFwith unusually high incidence rate in New Zealand. Adalimumab, an anti TNF agent has shown to be a safe and effective maintenance treatment for the response and remission in patients with CD.
Abraham, C., & Cho, J. H. (2009). Inflammatory Bowel Disease. New England Journal of Medicine, 361(21), 2066-2078. doi:10.1056/NEJMra0804647
Baumgart, D. C., & Carding, S. R. (2007). Inflammatory bowel disease: cause and immunobiology. The Lancet, 369(9573), 1627-1640. doi:http://dx.doi.org/10.1016/S0140-6736(07)60750-8
Bongartz, T., Sutton, A. J., Sweeting, M. J., Buchan, I., Matteson, E. L., & Montori, V. (2006). Anti-tnf antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: Systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA, 295(19), 2275-2285. doi:10.1001/jama.295.19.2275
Canavan, C., Abrams, K. R., & Mayberry, J. (2006). Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn’s disease. Alimentary Pharmacology & Therapeutics, 23(8), 1097-1104. doi:10.1111/j.1365-2036.2006.02854.x
Colombel, J. F., Sandborn, W. J., Rutgeerts, P., Enns, R., Hanauer, S. B., Panaccione, R., . . . Pollack, P. F. (2007). Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology, 132(1), 52-65. doi:10.1053/j.gastro.2006.11.041
Cosnes, J., Gower-Rousseau, C., Seksik, P., & Cortot, A. (2011). Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology, 140(6), 1785-1794. doi:10.1053/j.gastro.2011.01.055
Economou, M., Zambeli, E., & Michopoulos, S. (2009). Incidence and prevalence of Crohn’s disease and its etiological influences. Annals of gastroenterology, 22(3), 158-167.
Fireman, Z., Mahanjna, E., Broide, E., Shapiro, M., Fich, L., Sternerg, A., . . . Scapa, E. (2003). Diagnosing small bowel Crohn’s disease with wireless
capsule endoscopy. Gut, 52(3), 390-392.
Freeman, H. J. (2008). Colorectal cancer risk in Crohn’s disease. World Journal of Gastroenterology, 14(12), 1810-1811. doi:10.3748/wjg.14.1810
Gasche, C., Lomer, M. C. E., Cavill, I., & Weiss, G. (2004). Iron, anaemia, and inflammatory bowel diseases. Gut, 53(8), 1190-1197. doi:10.1136/gut.2003.035758
Gearry, R. B., & Day, A. S. (2008). Inflammatory bowel disease in New Zealand children—a growing problem. The New Zealand Medical Journal, 121, 5-8.
Gearry, R. B., Richardson, A., Frampton, C. M. A., Collett, J. A., Burt, M. J., Chapman, B. A., & Barclay, M. L. (2006). High Incidence of Crohn’s Disease in Canterbury, New Zealand: Results of an Epidemiologic Study. Inflammatory Bowel Diseases, 12(10), 936-943.
Hanauer, S. B. (2006). Inflammatory bowel disease: Epidemiology, pathogenesis, and therapeutic opportunities. Inflammatory Bowel Diseases, 12(5), S3-S9. doi:10.1097/01.MIB.0000195385.19268.68
Hanauer, S. B., Sandborn, W. J., Rutgeerts, P., Fedorak, R. N., Lukas, M., MacIntosh, D., . . . Pollack, P. (2006). Human Anti–Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in Crohn’s Disease: the CLASSIC-I Trial. Gastroenterology, 130(2), 323-333. doi:http://dx.doi.org/10.1053/j.gastro.2005.11.030
Hovde, Ø., & Moum, B. A. (2012). Epidemiology and clinical course of Crohn’s disease: Results from observational studies. World Journal of Gastroenterology : WJG, 18(15), 1723-1731. doi:10.3748/wjg.v18.i15.1723
Laing, B., Han, D. Y., & Ferguson, L. R. (2013). Candidate Genes Involved in Beneficial or Adverse Responses to Commonly Eaten Brassica Vegetables in a New Zealand Crohn’s Disease Cohort. Nutrients, 5(12), 5046-5064. doi:10.3390/nu5125046
Lennard-Jones, J. E. (1989). Classification of Inflammatory Bowel Disease. Scandinavian Journal of Gastroenterology, 24(sup170), 2-6. doi:10.3109/00365528909091339
Liu, J. Z., & Anderson, C. A. (2014). Genetic studies of Crohn’s disease: Past, present and future. Best Practice & Research Clinical Gastroenterology, 28(3), 373-386. doi:http://dx.doi.org/10.1016/j.bpg.2014.04.009
Loftus, E. V. (2004). Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology, 126(6), 1504-1517. doi:http://dx.doi.org/10.1053/j.gastro.2004.01.063
Mocko, P., Kawalec, P., & Pilc, A. (2016). Safety Profile of Biologic Drugs in the Therapy of Ulcerative Colitis: A Systematic Review and Network Meta-Analysis. Pharmacotherapy, 36(8), 870-879. doi:10.1002/phar.1785
Mow, W. S., Vasiliauskas, E. A., Lin, Y.-C., Fleshner, P. R., Papadakis, K. A., Taylor, K. D., . . . Targan, S. R. (2004). Association of antibody responses to microbial antigens and complications of small bowel Crohn’s disease. Gastroenterology, 126(2), 414-424. doi:http://dx.doi.org/10.1053/j.gastro.2003.11.015
New Zealand Formulary. (2017). Adalimumab.
Ng, S. C., Bernstein, C. N., Vatn, M. H., Lakatos, P. L., Loftus, E. V., Jr., Tysk, C., . . . Natural History Task Force of the International Organization of Inflammatory Bowel, D. (2013). Geographical variability and environmental risk factors in inflammatory bowel disease. Gut, 62(4), 630-649. doi:10.1136/gutjnl-2012-303661
Parameswaran, N., & Patial, S. (2010). Tumor Necrosis Factor-α Signaling in Macrophages. Critical reviews in eukaryotic gene expression, 20(2), 87-103.
Peyrin–Biroulet, L., Deltenre, P., de Suray, N., Branche, J., Sandborn, W. J., & Colombel, J. F. (2008). Efficacy and Safety of Tumor Necrosis Factor Antagonists in Crohn’s Disease: Meta-Analysis of Placebo-Controlled Trials. Clinical Gastroenterology and Hepatology, 6(6), 644-653. doi:http://dx.doi.org/10.1016/j.cgh.2008.03.014
PHARMAC. (2017). Proposal relating to the funding of TNF inhibitors (Humira and Enbrel) and Gabapentin (neurontin). Retrieved from https://www.pharmac.govt.nz/news/consultation-2015-07-14-tnf-inhibitors/
Podolsky , D. K. (1991). Inflammatory Bowel Disease. New England Journal of Medicine, 325(14), 1008-1016. doi:10.1056/nejm199110033251406
Rutgeerts, P., Vermeire, S., & Van Assche, G. (2009). Biological therapies for inflammatory bowel diseases. Gastroenterology, 136(4), 1182-1197. doi:10.1053/j.gastro.2009.02.001
Sandborn, W. J., Hanauer, S. B., Rutgeerts, P., Fedorak, R. N., Lukas, M., MacIntosh, D. G., . . . Pollack, P. F. (2007). Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut, 56(9), 1232-1239. doi:10.1136/gut.2006.106781
Sandborn, W. J., Rutgeerts, P., Enns, R., & et al. (2007). Adalimumab induction therapy for crohn disease previously treated with infliximab: A randomized trial. Annals of Internal Medicine, 146(12), 829-838. doi:10.7326/0003-4819-146-12-200706190-00159
Sartor, R. B. (2006). Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nature Clinical Practice Gastroenterology and Hepatology, 3(7), 390-407. doi:10.1038/ncpgasthep0528
Sheehan, A., Warren, B., Gear, M., & Shepherd, N. (1992). Fat‐wrapping in Crohn’s disease: pathological basis and relevance to surgical practice. British Journal of Surgery, 79(9), 955-958.
Su, H. Y., Gupta, V., Day, A. S., & Gearry, R. B. (2016). Rising incidence of inflammatory bowel disease in Canterbury, New Zealand. Inflammatory Bowel Diseases, 22(9), 2238-2244.
Thia, K. T., Sandborn, W. J., Lewis, J. D., Loftus, E. V., Jr., Feagan, B. G., Steinhart, A. H., . . . Sands, B. E. (2008). Defining the optimal response criteria for the Crohn’s disease activity index for induction studies in patients with mildly to moderately active Crohn’s disease. American Journal of Gastroenterology, 103(12), 3123-3131. doi:10.1111/j.1572-0241.2008.02176.x
Thomas, G., Lewis-Morris, T., Rowbotham, D., Whiteside, C., Joyce, S., Innes, S., . . . Gearry, R. B. (2014). Adalimumab for Crohn’s disease in New Zealand – a prospective multicentre experience. The New Zealand Medical Journal, 127(1396), 23-33. doi:http://ezproxy.auckland.ac.nz/login?url=https://search-proquest-com.ezproxy.auckland.ac.nz/docview/1539626958?accountid=8424
Timmer, A., Sutherland, L. R., & Martin, F. (1998). Oral contraceptive use and smoking are risk factors for relapse in Crohn’s disease. Gastroenterology, 114(6), 1143-1150. doi:http://dx.doi.org/10.1016/S0016-5085(98)70419-6
Triester, S. L., Leighton, J. A., Leontiadis, G. I., Gurudu, S. R., Fleischer, D. E., Hara, A. K., . . . Sharma, V. K. (2006). A Meta-Analysis of the Yield of Capsule Endoscopy Compared to Other Diagnostic Modalities in Patients with Non-Stricturing Small Bowel Crohn’s Disease. The American Journal of Gastroenterology, 101(5), 954-964. doi:http://dx.doi.org/10.1111/j.1572-0241.2006.00506.x
Triggs, C. M., Munday, K., Hu, R., Fraser, A. G., Gearry, R. B., Barclay, M. L., & Ferguson, L. R. (2010). Dietary factors in chronic inflammation: food tolerances and intolerances of a New Zealand Caucasian Crohn’s disease population. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 690(1-2), 123-138. doi:10.1016/j.mrfmmm.2010.01.020
Watanabe, T., Kitani, A., Murray, P. J., & Strober, W. (2004). NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nature Immunology, 5(8), 800-808. doi:10.1038/ni1092
The CDAI consists of eight variables and the score can range from 0 to 600 points.
|Variable Number||Variable Description||Multiplier|
|1||No. of liquid or soft stools (over 7 days)||X2|
|2||Abdominal pain, (sum of scores over 7 days) 0=none, 1=mild, 2=moderate, 3=severe||X5|
|3||General well-being, Sum of 7 daily ratings (0=generally well, 1= slightly under par, 2= poor, 3= very poor, 4= terrible)||X7|
|4||No. of listed complications on day of assessment (arthritis, iriarthralgia, iritis or uveitis, erythema nodosum or pyoderma gangrenosum or aphthous stomatitis, anal fissure, fever >37.8C||X20|
|5||Use of diphenoxylate or loperamide for diarrhoea (0=N, 2= Y)||X30|
|6||Abdominal mass (0-no, 2= questionable, 5= definite)||X10|
|7||Haemocrit: male, 47-Hct [%], Females 42-Hct [%]||X6|
|8||Body Weight (1 – weight/standard weight) x 100 (add or subtract according to sign)||X1|
(Thia et al., 2008)
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