Ulcerative Colitis and New Possible Treatments Written by TEJINDER MOHAN AGGRWAL [Stream:Allopathy] Friday, 29th January 2010 Ulcerative Colitis and New Possible Treatments Ulcerative colitis is a disease that causes inflammation and sores, called ulcers, in the lining of the rectum and colon. Ulcers form where inflammation has killed the cells that usually line the colon, then bleed and produce pus. Inflammation in the colon also causes the colon to empty frequently, causing diarrhea. When the inflammation occurs in the rectum and lower part of the colon it is called ulcerative proctitis. If the entire colon is affected it is called pancolitis. If only the left side of the colon is affected it is called limited or distal colitis. Ulcerative colitis is an inflammatory bowel disease (IBD), the general name for diseases that cause inflammation in the small intestine and colon. It can be difficult to diagnose because its symptoms are similar to other intestinal disorders and to another type of IBD called Crohn’s disease. Crohn’s disease differs because it causes inflammation deeper within the intestinal wall and can occur in other parts of the digestive system including the small intestine, mouth, esophagus, and stomach. Ulcerative colitis can occur in people of any age, but it usually starts between the ages of 15 and 30, and less frequently between 50 and 70 years of age. It affects men and women equally and appears to run in families, with reports of up to 20 percent of people with ulcerative colitis having a family member or relative with ulcerative colitis or Crohn’s disease. A higher incidence of ulcerative colitis is seen in Whites and people of Jewish Symptoms of Ulcerative Colitis ? The most common symptoms of ulcerative colitis are abdominal pain and bloody diarrhea. Patients also may experience • anemia • fatigue • weight loss • loss of appetite • rectal bleeding • loss of body fluids and nutrients • skin lesions • joint pain • growth failure (specifically in children) About half of the people diagnosed with ulcerative colitis have mild symptoms. Others suffer frequent fevers, bloody diarrhea, nausea, and severe abdominal cramps. Ulcerative colitis may also cause problems such as arthritis, inflammation of the eye, liver disease, and osteoporosis. It is not known why these problems occur outside the colon. Scientists think these complications may be the result of inflammation triggered by the immune system. Some of these problems go away when the colitis is treated. Causes ulcerative colitis? Many theories exist about what causes ulcerative colitis. People with ulcerative colitis have abnormalities of the immune system, but doctors do not know whether these abnormalities are a cause or a result of the disease. The body’s immune system is believed to react abnormally to the bacteria in the digestive tract. Ulcerative colitis is not caused by emotional distress or sensitivity to certain foods or food products, but these factors may trigger symptoms in some people. The stress of living with ulcerative colitis may also contribute to a worsening of symptoms. Diagnosis Many tests are used to diagnose ulcerative colitis. A physical exam and medical history are usually the first step. Blood tests may be done to check for anemia, which could indicate bleeding in the colon or rectum, or they may uncover a high white blood cell count, which is a sign of inflammation somewhere in the body. A stool sample can also reveal white blood cells, whose presence indicates ulcerative colitis or inflammatory disease. In addition, a stool sample allows the doctor to detect bleeding or infection in the colon or rectum caused by bacteria, a virus, or parasites. A colonoscopy or sigmoidoscopy are the most accurate methods for making a diagnosis of ulcerative colitis and ruling-out other possible conditions, such as Crohn’s disease, diverticular disease, or cancer. For both tests, the doctor inserts an endoscope—a long, flexible, lighted tube connected to a computer and TV monitor—into the anus to see the inside of the colon and rectum. The doctor will be able to see any inflammation, bleeding, or ulcers on the colon wall. During the exam, the doctor may do a biopsy, which involves taking a sample of tissue from the lining of the colon to view with a microscope. Sometimes x rays such as a barium enema or CT scans are also used to diagnose ulcerative colitis or its complications. A major genetic link to the development of Crohn's disease and ulcerative colitis, as well as other inflammatory diseases, has been revealed in a recent study. "This genetic discovery is special because it may have a rapid impact on diagnosis and treatment of these chronic digestive diseases," says Jonathan Braun, M.D., Ph.D., Chair of the National Scientific Advisory Committee of the Crohn's & Colitis Foundation of America (CCFA) Previous genetic studies uncovered a link between Crohn's and variants of the gene CARD15 (also known as NOD2), but this gene plays a role in only some Crohn's patients, and does not affect the risk for colitis. The new discovery, which involves a gene called the interleukin-23 (IL-23) receptor, has a much larger effect on these inflammatory diseases. Interleukin (IL)-23 is a heterodimeric cytokine closely related to IL-12. Yet, despite a strong structural relationship that includes a shared p40 subunit, this does not translate into functional similarity. In fact, the opposite is true, in that these two cytokines appear to have profoundly different roles in regulating host immune responses. It is now clear that IL-23 has key roles in autoimmune destruction in experimental allergic encephalomyelitis, collagen-induced arthritis and inflammatory bowel disease. IL-23 drives the development of autoreactive IL-17-producing T cells and promotes chronic inflammation dominated by IL-17, IL-6, IL-8 and tumor necrosis factor as well as neutrophils and monocytes. It is unlikely that IL-23 and its downstream effects evolved just to cause autoimmunity, but its real benefit to the host and the lineage relationship between IL-17-producing cells and T helper 1 cells remain unclear. By comparing the pathophysiological function of IL-12 and IL-23 in the context of host defense and autoimmune inflammation, we are beginning to understand the novel IL-23-IL-17 immune pathway. Colon Cancer: About 5 percent of people with ulcerative colitis develop colon cancer. The risk of cancer increases with the duration of the disease and how much the colon has been damaged. For example, if only the lower colon and rectum are involved, the risk of cancer is no higher than normal. However, if the entire colon is involved, the risk of cancer may be as much as 32 times the normal rate. Sometimes precancerous changes occur in the cells lining the colon. These changes are called "dysplasia." People who have dysplasia are more likely to develop cancer than those who do not. Doctors look for signs of dysplasia when doing a colonoscopy or sigmoidoscopy and when examining tissue removed during these tests. According to the 2002 updated guidelines for colon cancer screening, people who have had IBD throughout their colon for at least 8 years and those who have had IBD in only the left colon for 12 to 15 years should have a colonoscopy with biopsies every 1 to 2 years to check for dysplasia. Differential Diagnosis: The entire length of the colon, starting at the rectosigmoid junction and ending at the cecum, can be visualized by transabdominal sonography after retrograde water instillation into the colon. By this method, termed hydrocolonic sonography, it is possible to evaluate in detail the lumen, the colon wall, and the surrounding tissue. Five layers of different echogenicity can be differentiated within the colon wall. METHODS: In a prospective study of 440 patients, it had been compared the value of conventional abdominal sonography and hydrocolonic sonography with that of colonoscopy, in the diagnosis and differential diagnosis of ulcerative colitis and colonic Crohn's disease. RESULTS: In 93% of patients with Crohn's disease, the normal five-layer structure of the colonic wall was no longer in evidence, and the wall appeared hypoechogenic and clearly thickened. In patients with ulcerative colitis, the five-layer structure could clearly be discerned, and although the colon wall remained hypoechogenic, it was only moderately thickened. Colonic Crohn's disease and ulcerative colitis were detectable by hydrocolonic sonography, with a sensitivity of 96% and 91%, respectively. The sensitivity achieved by conventional abdominal sonography is only 71% and 62% respectively. Furthermore, hydrocolonic sonography made possible the differentiation of Crohn's disease from Ulcerative colitis in 93% of the cases. Pathological Diagnosis: Crohn's disease and ulcerative colitis are distinct entities, but in 5 to 10% of patients and resected specimens, a clear separation may not be possible. The pathological diagnosis and differential diagnosis of Crohn's disease, including ulcerative colitis, indeterminate colitis and other diseases may mimic Crohn's disease. It is often difficult or impossible to distinguish diversion colitis and pouchitis from recurrence of Crohn's disease. Increased expression of CD44v6 and CD44v3 in Ulcerative Colitis but not colonic Crohn's Disease: Immune mechanisms, possibly involving cell-surface molecules such as CD44, have been invoked to explain the pathogenesis of inflammatory bowel disease. Monoclonal antibodies were used against epitopes encoded within the variable region of CD44 to investigate CD44 isoform expression in colon, small intestine, and liver in patients with various intestinal disorders and in controls. Biopsy samples from patients with ulcerative colitis showed significantly increased epithelial expression of CD44 isoforms containing the v6 and v3 epitopes, detected with antibodies 2F10 and 3G5, respectively. CD44v6 was detected on colonic crypt epithelial cells in 23 of 25 ulcerative colitis samples compared with 3 of 18 colonic Crohn's disease samples (p = 3.0 x 10(-6); odds ratio 57.5 [95% CI 6.83-702]) and 3 of 52 controls (22 normal colon, 10 infective colitis, 2 radiation colitis, and 18 colonic Crohn's disease; p < 1 x 10(-8); odds ratio 199 [25.5-2294]). No significant expression of CD44v6, CD44v3, or CD44v8/9 was found in samples of normal proximal colon from 4 patients with distal ulcerative colitis, whereas samples from the affected area showed staining for CD44v6 and CD44v3. No expression of CD44 variants was found in 15 samples of normal small intestine, 11 small-bowel pouchitis, 8 coeliac disease, 3 small-bowel Crohn's disease, 6 normal liver, 6 primary biliary cirrhosis, or 9 primary sclerosing cholangitis. The high intensity of CD44v6 and v3 epitope expression on crypt epithelial cells in ulcerative colitis suggests that CD44 isoforms may have an important role in ulcerative colitis. Their detection could have diagnostic potential in differentiating ulcerative colitis from other forms of colonic inflammation including Crohn's disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed &cmd=Retrieve&dopt=abstractplus&list_uids=7537840 Poor diagnostic value of colonic CD44v6 expression and serum concentrations of its soluble form in the differentiation of Ulcerative Colitis from Crohn's disease: Increased expression of CD44v6 on colonic crypt epithelial cells in ulcerative colitis has been suggested as a diagnostic tool to distinguish ulcerative colitis from colonic Crohn's disease. AIMS: To investigate colonic CD44v6 expression and serum concentrations of soluble CD44v6 (sCD44v6) in patients with ulcerative colitis and Crohn's disease. METHODS: Colonic biopsy samples were obtained from 16 patients with ulcerative colitis, 13 with ileocolonic Crohn's disease, and 10 undergoing polypectomy. Serum samples were obtained from 15 patients with active ulcerative colitis, 20 with active Crohn's disease, and 20 healthy donors. Colonic CD44v6 expression was evaluated immunohistochemically by monoclonal antibody 2F10 and the higher affinity monoclonal antibody VFF18. Serum sCD44v6 concentrations were measured by ELISA. RESULTS: 2F10 stained colonic epithelium of inflamed ulcerative colitis and Crohn's disease samples in 80% and 40% of cases, respectively, and VFF18 in 95% and 87%, respectively. Both monoclonal antibodies displayed a sensitivity and specificity of 60% and 87% to differentiate ulcerative colitis from colonic Crohn's disease. Serum concentrations of sCD44v6 were lower in patients with ulcerative colitis (median 153 ng/ml; interquartile range (IQR) 122-211) compared with Crohn's disease (219; IQR 180-243) and healthy donors (221; IQR 197-241 (p = 0.002)). Its sensitivity and specificity to discriminate ulcerative colitis from Crohn's disease was 75% and 71%, respectively. CONCLUSION: Colonic CD44v6 and serum sCD44v6 concentrations do not facilitate reliable differential diagnosis between ulcerative colitis and Crohn's disease. Evaluation of serological markers to differentiate between ulcerative colitis and Crohn's disease: pANCA, ASCA and agglutinating antibodies to anaerobic coccoid rods The value of these serological tests in differentiating ulcerative colitis from Crohn's disease is limited when used separately but, by combining two or more tests, the positive predictive value and specificity can be improved substantially. These tests might be of help in studying disease heterogeneity, and may contribute to defining various subgroups of patients with different pathogeneses. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed &cmd=Retrieve&dopt=abstractplus&list_uids=12352222 Genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed &list_uids=8119534&dopt=Abstract Cytokine profile in colonic mucosa of ulcerative colitis correlates with disease activity and response to granulocytapheresis http://www.blackwell-synergy.com/links/doi/10.1111/j.1572-0241.2002.07029.x/abs/ Use of CT findings in differential diagnosis: The mean colon wall thickness in Crohn colitis (11.0 mm +/- 5.1) is significantly greater than in ulcerative colitis (7.8 mm +/- 1.9) (P < .002). Submucosal fat deposition, not observed in the acute colitis, is significantly present more oftenly in ulcerative (61%) than in Crohn colitis (8%) (P = .0001). Exclusive involvement of the right colon and small bowel was most frequent with Crohn and infectious colitis. Abscess was associated almost exclusively with Crohn colitis (35%) but was seen in one patient with radiation colitis. CONCLUSION: Although many CT findings in patients with colitis are nonspecific, some features are helpful in suggesting a specific diagnosis. Available treatment for ulcerative colitis: 1. Aminosalicylates: drugs that contain 5-aminosalicyclic acid (5-ASA), help control inflammation. Sulfasalazine is a combination of sulfapyridine and 5-ASA. 2. Corticosteroids such as prednisone, methylprednisone, and hydrocortisone also reduce inflammation. They may be used by people who have moderate to severe ulcerative colitis or who do not respond to 5-ASA drugs. 3. Immunomodulators such as azathioprine and 6-mercapto-purine (6-MP) reduce inflammation by affecting the immune system. These drugs are used for patients who have not responded to 5-ASAs or corticosteroids or who are dependent on corticosteroids. Immunomodulators are administered orally, however, they are slow-acting and it may take up to 6 months before the full benefit. 4. Surgery (a) Ileostomy, (b) Ileoanal anastomosis. New Possible Treatments: 1. Dr. Braun notes that while the disease state of all Crohn's and colitis patients is not likely to be driven by IL-23, the drugs necessary to affect change in the behavior of this protein receptor already exist. In fact, one such therapy was recently reported by a team at the National Institutes of Health (NIH). The investigators were able to show that therapy targeting p40 a subunit of IL-23 can inhibit the activity of IL-23 in Crohn's disease (Mannon P, N Engl J Med 351:2069, 2004). This genetic discovery is likely to accelerate tests of this and other drugs, and to better identify which patients will benefit from such diseases, and affects risk for both Crohn's and Colitis. "The genetic variants in the IL-23 receptor gene have been identified that confer increased risk for IBD, but we are most excited about our discovery of a genetic factor in the same gene that confers protection against developing IBD," said Dr. Duerr. "There is hope that ongoing research will tease out the specific downstream effects of these genetic variants so that this knowledge can be used to develop better, more targeted therapies for patients with IBD.”. 2. LCAP (Leucocytapheresis) Leukocyctapheresis (LCAP) is a blood purification treatment for ulcerative colitis (UC) [1]. LCAP is known to have a low incidence of side effects. LCAP is carried out using a column (Cellsorba E) filled with a non-woven fabric made up of polyester fibers. The fabric had a dual structure; an inner layer composed of superfine fibers 0.8-2.8 in diameter, and an outer layer composed of fibers 10-40 in diameter. The blood is filtrated from the outside into the inside of the non-woven fabric wound into a cylindrical shape in the column, and leukocyte components are removed. The blood, with leukocyte removed, is guided out from the column and heated, and the returned to the corresponding vein of the patient’s other arm or leg of the patient. The blood flow rate is set at 30-50 , and 2-3 L of blood is treated in each session of LCAP. The treatment is carried out for one hour per session once in a week, for 10 wks. 3. Non-pathogenic Escherichia coli versus Mesalazine for the treatment of ulcerative colitis: Ulcerative colitis has been suggested to be caused by infection and there is circumstantial evidence linking Escherichia coli with the condition. I had been tried to find out whether the administration of a non-pathogenic strain of E. coli (Nissle 1917) is as effective as mesalazine in preventing relapse of ulcerative colitis. It has also been examined whether the addition of E. coli to standard medical therapy increased the chance of remission of active ulcerative colitis. Trial study: This was a single-centre, randomised, double-dummy study in which 120 patients with active ulcerative colitis were invited to take part. 116 patients accepted; 59 were randomised to mesalazine and 57 to E. coli. All patients also received standard medical therapy together with a 1-week course of oral gentamicin. After remission, patients were maintained on either mesalazine or E. coli and followed up for a maximum of 12 months. A two-stage, conditional, intention-to-treat analysis was done. FINDINGS: 44 (75%) patients in the mesalazine group attained remission compared with 39 (68%) in the E. coli group. Mean time to remission was 44 days (median 42) in the mesalazine group and 42 days (median 37) for those treated with E. coli. In the mesalazine group, 32 (73%) patients relapsed compared with 26 (67%) in the E. coli group. Mean duration of remission was 206 days in the mesalazine group (median 175) and 221 days (median 185) in the E. coli group. INTERPRETATION: The results suggest that treatment with a non-pathogenic E. coli has an equivalent effect to mesalazine in maintaining remission of ulcerative colitis. The beneficial effect of live E. coli may provide clues to the cause of Ulcerative Colitis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed &list_uids=10466665&dopt=Citation References: http://ccfa.i33.com/media/pdf/profchallenges.pdf http://www3.interscience.wiley.com/cgi-bin/abstract/108061210/ABSTRACT?CRETRY=1&SRETRY=0 http://jimmunol.highwire.org/cgi/content/abstract/172/1/525 http://jimmunol.highwire.org/cgi/content/abstract/170/11/5438 http://jimmunol.highwire.org/cgi/content/abstract/173/3/1887 http://www.journals.uchicago.edu/cgi-bin/resolve?id=doi:10.1086/425021 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed &list_uids=16290228&dopt=Citation http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed &list_uids=15158199&dopt=Abstract&holding=f1000,f1000m,isrctn http://jimmunol.highwire.org/cgi/content/abstract/166/12/7563 Ubiquitous Transgenic Expression of the IL-23 Subunit p19 Induces Multi-organ inflammation, Runting, Infertility, and Premature Death Dr Tejinder M Aggrwal GAMS, MBBS & RESEARCH ASSOCIATE CSE & BIO-INFORMATICS FAU BOCA RATON 33431 FL USA