Both ulcerative colitis and Crohn’s disease are diseases of modern life. UC has been known since 1800s and CD tends to occur more in the West than in Asia. Removing the appendix in early life reduces the incidence of UC but not CD. Diets rich in fats and sugar are predisposing to both diseases. The discovery that NOD2 variants are associated with susceptibility to Crohn’s disease opened a new era in the study of the genetic basis of inflammatory bowel disease. In studies of twins, there is stronger concordance with Crohn’s disease than with ulcerative colitis, and the identification of a large number of susceptibility loci for Crohn’s disease in early genome wide association studies suggested that genetic influences play a greater role in Crohn’s disease than in ulcerative colitis.
It has also been postulated that alterations in the composition of the gut microbiota, defects in mucosal immunity, or the two factors combined could lead to ulcerative colitis; however, supportive evidence is sparse. There is a consensus that the density of microbiota is greater in patients with ulcerative colitis or Crohn’s disease than in healthy control subjects, but whether there are reproducible, disease-specific alterations is unclear. The only ulcerative colitis–associated antibody is perinuclear antineutrophil cytoplasmic antibody (pANCA), which recognizes nuclear antigens that may cross-react with bacterial antigens. Autoimmunity may play a role in ulcerative colitis. In addition to pANCA, this disease is characterized by circulating IgG1 antibodies against a colonic epithelial antigen that is shared with the skin, eye, joints, and biliary epithelium.
Abnormalities in humoral and cellular adaptive immunity occur in ulcerative colitis. Elevated IgM, IgA, and IgG levels are common in inflammatory bowel disease, but there is a disproportionate increase in IgG1 antibodies in ulcerative colitis.
Abnormalities of adaptive immunity that differentiate ulcerative colitis from Crohn’s disease are defined by mucosal CD4+ T cells, which were initially divided into two lineages: Th1 and type 2 helper T cells (Th2). Crohn’s disease is a Th1-like condition, on the basis of evidence of increased production of interferon-γ. In contrast, ulcerative colitis represents an atypical Th2 response, as indicated by the presence of nonclassical natural killer T cells in the colon that secrete abundant interleukin-13, which mediates epithelial-cell cytotoxicity, apoptosis, and epithelial-barrier dysfunction.
Bloody diarrhea with or without mucus is the hallmark of ulcerative colitis. The onset is typically gradual, often followed by periods of spontaneous remission and subsequent relapses. Active disease is manifested as mucosal inflammation commencing in the rectum (proctitis) and in some cases spreading to the rest of the colon.
Although proctitis is frequently associated with fecal urgency and the passage of fresh blood, constipation may paradoxically occur. Proctosigmoiditis, left-sided colitis, extensive colitis, or pancolitis may lead to diarrhea, frequent evacuations of blood and mucus, urgency or tenesmus, abdominal pain, fever, malaise, and weight loss, depending on the extent and severity of the disease. A small area of inflammation surrounding the appendiceal orifice (cecal patch) can be identified in patients with left-sided ulcerative colitis and in those with proctitis or proctosigmoiditis. The prognosis for patients with ulcerative colitis is generally good during the first decade after diagnosis, with a low rate of colectomy; over time, remission occurs in most patients.
Acute complications, such as severe bleeding and toxic megacolon may occur in patients with severe disease. Risk factors for cancer include a long duration of disease, regardless of clinical activity; extensive involvement; a young age at onset; severe inflammation; the presence of primary sclerosing cholangitis; and a family history of colorectal cancer.
An accurate diagnosis of ulcerative colitis involves defining the extent and severity of inflammation, and this information provides the basis for selecting the most appropriate treatment and for predicting the patient’s prognosis. Both endoscopy and biopsy are required to determine specific histologic characteristics; radiologic and ultra sonographic examinations are not critical but may be useful.
Colonoscopy shows a uniformly inflamed mucosa that starts at the anorectal verge and extends proximally, with an abrupt or a gradual transition from affected to normal mucosa. In mild ulcerative colitis, the mucosa has a granular, erythematous appearance, with friability and loss of the vascular pattern. In moderate disease, erosions or microulcerations are evident, whereas in severe ulcerative colitis, shallow ulcerations with spontaneous bleeding are generally seen. In pancolitis, inflammation stops at the ileocecal valve, with occasional limited involvement of the distal ileum, a condition known as backwash ileitis.
Colonoscopy helps to differentiate ulcerative colitis from Crohn’s disease, which is typically characterized by rectal sparing, aphthous ulcers, skip lesions (areas of inflammation alternating with normal mucosa), a cobblestone pattern, and longitudinal, irregular ulcers.
In patients with cycles of inflammation and healing and in those with chronic, unremitting inflammation, colonoscopy may reveal pseudo polyps or mucosal bridging. If a stricture is detected, multiple biopsies are mandatory to rule out malignant disease; biopsies are also required for surveillance of dysplasia in patients who have the disease for longer than 8 years. Newer endoscopic techniques that are gaining acceptance, such as chromoendoscopy, narrow-band imaging, and auto-fluorescence imaging, may better delineate suspicious mucosal patterns and improve the detection of dysplasia.
In ulcerative colitis, inflammation is characteristically restricted to the mucosal layer, with infiltrates varying in density and composition during active disease or stages of remission. Infiltrates consist primarily of lymphocytes, plasma cells, and granulocytes; the last are being particularly prominent during acute flare-ups and accumulate in crypt abscesses. Other typical features include goblet-cell depletion, distorted crypt architecture, diminished crypt density, and ulcerations. However, epithelioid granulomas, which are typical of Crohn’s disease, are not present.
Looking for epithelial dysplasia is critical, given the risk of cancer in patients with long-standing ulcerative colitis; however, dysplasia can occur at any stage without indicating malignant transformation. There are no exact criteria for the diagnosis of ulcerative colitis, but in most cases, the presence of two or three of the aforementioned histologic features will suffice.
Laboratory measurements are helpful in assessing and monitoring disease activity and in differentiating ulcerative colitis from other forms of colitis. Blood counts and measurements of the erythrocyte sedimentation rate and the level of fecal lactoferrin or calprotectin help determine the severity of the inflammation. Stool cultures for Clostridium difficile, campylobacter species, and Escherichia coli 0157:H7 are recommended to rule out an infectious cause or complication. Patients with severe, refractory disease should be assessed for cytomegalovirus infection by means of histologic, immunochemical, serologic, culture, or DNA testing.56 A positive test for ASCA or pANCA is not diagnostic, given the limited sensitivity and specificity of the tests; when they are performed in combination, however, the results may help differentiate among ulcerative colitis, Crohn’s disease, and indeterminate colitis.
Induction of Remission
- Sulfasalazine and 5-aminosalicylates (mesalamine, olsalazine, and balsalazide), given orally, rectally (by means of suppository or enema), or both, represent first-line treatment for ulcerative colitis, with an expected remission rate of about 50%.
- Mild-to-moderate proctitis can be treated with mesalamine suppositories (1 g per day) or enemas (2 to 4 g per day); clinical remission occurs in most patients within 2 weeks, with repeated treatments as needed.
- If this fails, 5-aminosalicylate enemas (2 to 4 g per day) or glucocorticoid enemas (hydrocortisone at a dose of 100 mg per day, or new preparations such as budesonide or beclomethasone) are a next step.
- Patients who do not have a response to rectally administered agents may be given oral glucocorticoids (up to 40 mg of prednisone or its equivalent).
- Mild-to-moderate left-sided colitis to extensive ulcerative colitis is initially best treated with a combination of rectal and oral 5-aminosalicylate (up to 4.8 g per day).
- Patients with mild-to-moderate ulcerative colitis that is refractory to rectal therapies and to oral 5-aminosalicylate are candidates for oral glucocorticoids or immunosuppressive agents (azathioprine or 6-mercaptopurine); those who do not have a response to maximal doses of 5-aminosalicylate or oral glucocorticoids should be given intravenous glucocorticoids.
- A good therapeutic option appears to be infliximab, a monoclonal antibody against TNF-α, administered at a dose of 5 mg per kilogram of body weight at 0, 2, and 6 weeks. Infliximab in combination with azathioprine (2.5 mg per kilogram) was reported to be superior to infliximab or azathioprine monotherapy for inducing glucocorticoid-free remission in patients with moderate-to-severe ulcerative colitis.
- Many specialists suggest that patients with extensive, severe disease receive a 5-day to 7-day course of intravenous glucocorticoids; if the disease is unresponsive, then intravenous cyclosporine (2 mg per kilogram) or infliximab is usually the next step. Although cyclosporine can be effective, it generally delays rather than prevents subsequent colectomy.
After remission has been achieved, the goal is to maintain the symptom-free status, which can be accomplished with various medications, with the exception of glucocorticoids, which have no place in maintenance therapy, given the marked side effects associated with their long-term use. Both oral and rectal 5-aminosalicylate have greater efficacy than placebo for maintenance of remission in patients with distal disease. Thiopurines (e.g., azathioprine at a dose of 2.5 mg per kilogram or 6-mercaptopurine at a dose of 1.5 mg per kilogram) are recommended when 5-aminosalicylate is ineffective or not tolerated or when the patient is glucocorticoid-dependent, although it may take several months before their maximal effectiveness is reached.
Unlike Crohn’s disease, ulcerative colitis may respond to probiotic therapy. For example, Escherichia coli strain Nissle 1917 (200 mg per day) is not less effective than 5-aminosalicylate (1.5 g per day) for maintaining remission, and the probiotic VSL#3 (3600 billion colony-forming units per day for 8 weeks) in conjunction with 5-aminosalicylate can help induce remission in mild-to-moderate ulcerative colitis.
Ulcerative colitis is generally easy to diagnose, and conventional step-up therapy is adequate for managing mild-to-moderate disease activity. Nevertheless, various important challenges remain. Several questions regarding the pathogenesis of ulcerative colitis remain to be answered. Why is inflammation restricted to the mucosal layer? Are colonic epithelial cells specific targets of an immune response? How does the luminal microbiota relate to the inflammatory response? Why does pouchitis develop in patients with an IPAA?
Many patients with ulcerative colitis still receive suboptimal doses of medications (particularly the aminosalicylates), continue to take glucocorticoids for exceedingly long intervals, or switch to biologic agents before immunosuppressive therapy has been optimized. In many cases, colectomy is a reasonable option, yet patients and clinicians alike remain reluctant to accept it.
Adalimumab, a different anti-TNF-α antibody, is reported to induce remission, and antibodies such as MLN0002 and PF-00547659, which prevent homing of leukocytes to the gut, have shown preliminary efficacy in active ulcerative colitis.