Ulcerative colitis

Ulcerative colitis is limited to the colon, with superficial mucosal inflammation that extends proximally in a contiguous manner, and can lead to ulcerations, severe bleeding, toxic megacolon, and fulminant colitis. 

Affects approximately 1 million Americans.

Incidence increasing in recent decades.

Typically presents in the second or third decade of life.

The natural history of the disease is one of periods of remission and flares.

Characterized by bloody diarrhea, anemia, and abdominal pain.

Associated with the risk of colectomy and increased risk of colorectal cancer.

Exact pathogenesis is unknown, but there are a number of genetic and environmental factors that increase the risk.

10 to 25% of patients with IBD have a first degree relative with the disease.

UC more common in patients of Jewish origin compared with non-Jews.

Is less frequently seen in African-Americans and Hispanics.

HLA-DqA1 variants appear most strongly associated with UC.

Other genetic pathways involved epithelial barrier function, such as CHD1 and LAMB1, and those encoding for cited kinds and inflammatory markers.

More common among whites, than blacks, and females more commonly affected than males.

Highest incidence and prevalence of inflammatory bowel disease seen in northern Europe and North America with the lowest incidence in Asia.

A meta-analysis confirmed the presence of 47 loci with ulcerative colitis, of which 19 are specific, and 28 are shared with Crohn’s disease (Anderson, CA al).

Its pathogenesis is driven by gene environment interaction leading to an abnormal immune system response to the intestinal microbiome.

More than 200 genetic loci have been associated.

Environmental exposures predispose individuals to UC by influencing the diversity and composition of the 1 trillion bacteria, viruses, and fungi that form the intestinal microbiome.

Reduces life expectancy by 4 to 6 years

Peak onset of disease between 20-25 years, but can arise in younger and older individuals.

Less prevalent than Crohn’s disease among children.

Worldwide more common than Crohn’s disease.

Both Crohn’s disease and UC more common in the industrialized world particularly North America and Western Europe.

Majority of patients have inflammation in their rectum with subsequent spreading along the colon to varying extent.

The migration of leukocytes into inflamed intestinal tissue is regulated by the Alpha4 beta7 integrin, a cell surface glycoprotein expressed on circulating B and T lymphocytes.

The alpha4 beta7 integrin interacts with mucosal addressin-cell adhesion molecule (MAdCAM-1) on intestinal vasculature.

Human tumor necrosis factor – like cytokine 1A (TL1A) is implicated in the pathogenesis of inflammatory bowel disease.

Inflammation may be limited to the rectum, i.e., proctitis, or rectum and sigmoid colon or rectum, sigmoid and descending colon.

A disease of the mucosa that is less prone to complications than Crohn’s disease.

In many patients the course is mild.

Extensive colitis refers to involvement of at least 2/3 of the colon.

Pan colitis refers to involvement of the entire colon.

A chronic process with periods of active disease and periods of mild or inactive disease.

No specific diagnoses increased risk of UC.

UC disease typically begins gradually and progresses for several weeks.

Felt to be an inappropriate response of the immune system to bacteria normally present in the colon.

Risk factors may be related to alterations of the gut microbiome or disruption in the intestinal mucosa.

No single bacteria identified to cause this process.

Intestinal infections, nonsteroidal anti-inflammatory drugs, and antibiotics have been implicated in the development of inflammatory bowel disease.

The association between enteric infection in the development of IBD seen most commonly within one year of illness with salmonella or Campylobacter.

The Nurses Health Registry found women using nonsteroidal anti-inflammatory drugs for at least 15 days are at increased risk of developing IBD.

Women taking oral doses of nonsteroidal anti-inflammatory drugs for a long period time are at higher risk for IBD.

Antibiotic exposure, particularly to tetracyclines, is associated with an increased risk of UC.

Other risk factors include homeowner replacement therapy and oral contraceptives.

Less common in smokers and patients who have the disease and stop smoking have an increased risk of a flare of the disease.

Symptoms include diarrhea, diarrhea with blood, and abdominal pain.

Typical presenting symptoms include: abdominal pain, bloody diarrhea, urgency, and tenesmus.

Rectal bleeding is reported in more than 90% of patients and varies by disease severity from trace to frank bleeding.

More than 90% of patients experience decreasing stool consistency and increased frequency occurring more than three times per day.

Bowel urgency occurs in 75 to 90% of patients.

Common intestinal symptoms include tenesmus, fecal, incontinence, nocturnal, bowel movements, and crampy abdominal pain.

Individuals with severe inflammation throughout the colon may experience fatigue, fever, dehydration, and weight loss.

Extraintestinal manifestations may be present as well on presentation.

Extraintestinal manifestations occur in approximately 27% of patients with UC and 1/4 of extra intestinal manifestations occur prior to the diagnosis.

Extra intestinal manifestations primarily affects the skin, joints, eyes, and liver.

Erythema nodosum and then pyoderma gangrenosum are the two most common immunologic skin lesions:occur in about 1% of patients with UC.

Erythema nodosum usually follows the activity of the gastrointestinal disease, while pyoderma gangrenosum is often more independent.

Arthritis is the most common extra intestinal manifestation.

Sacroiliitis and ankylosing spondylitis occur in 4% of patients with UC and are independent of bowel disease activity.

Peripheral arthritis occurs at approximately 11% of patients with UC.

Patients with severe disease can have as many as 15-20 stools per day.

Patients with disease localized to the rectum may have constipation.

Lower abdominal crampy pain is common and is typically note to be present on the left side of the abdomen, but may involve the entire abdomen.

30-50% of patients have extra-intestinal symptoms involving the joints with arthritis, skin rashes and eye irritation.

Ocular manifestations of you UC occur in 2% of patients and may precede bowel problems.

During flares fever may be noted.

Anemia commonly related to gastrointestinal blood loss.

May be associated with psychological distress, malnutrition and work disability.

Associated with decreased fertility.

Approximately 15% of patients have a severe attack requiring hospitalization at some time during their illness.

Symptomatic patients frequently have anemia, elevated ESR or CRP changes.

PANCA antibodies are present in 50-80% of patients with UC.

Anti-Saccharomyces cerevisiae antibodies present in 5-15% of patients with UC.

Increased risks for developing colon cancer and hepatobiliary carcinoma.

The rate of colectomy 20 years after diagnosis is nearly 15%, and has not decline over the last 10 years.

Increased risk of colorectal cancer is estimated to be 7-14% after 25 years of disease.

Rates of colorectal cancer may as be as high as 30% when disease duration is > 35 years.

Most accurate method for diagnosis is colonoscopy, with findings of mucosal swelling, inflammation, bleeding, ulcerations in a continuous pattern.

UC is classified by its location, because the extent of chronic involvement correlates with disease, severity and influences management.

The Montreal classification: three segments-proctitis, inflammation limited to the rectum, left-sided colitis inflammation past the rectum, but not beyond the splenic  flexure and extensive pancolitis, inflammation past the splenic flexure involving the entire colon, respectively.

It is estimated a diagnosis that 29.4% of cases have proctitis, 40.1% have left-sided, colitis, and 30.5% have extensive colitis.

Disease extent may alter overtime, up to 30% of the individuals presenting with a more extensive form of UC 10 years after diagnosis.

UC risk stratification, follows a gradient from mild to moderate to severe disease based on clinical and endoscopic evaluation which guides management.

Diagnosis

Diagnosis of UC is based on a combination of gastrointestinal symptoms, biochemical markers, colonoscopy, and pathology.

With increasing disease, severity, anemia, leucocytosis, thrombocytosis, and an elevated C-reactive protein can be found.

Stool biomarkers: calprotectin can distinguish UC from functional disorders of the G.I. tract.

Stool calprotectin, a protein released by neutrophils has a sensitivity of 0.89 and a specificity of 0.81 in differentiating  inflammatory bowel disease from non-inflammatory bowel diagnoses using 50 µg per gram cutoff.

Biopsy of the colonic tissue reveals inflammation and confirms the diagnosis of the disease.

Baxiopsy of inflamed mucosa reveals chronic architectural changes with distorted crypts and branching glands.

Endoscopic appearance of UC begins at the anorectal junction with continuous, circumferential, and diffuse inflammation without a break until the clear transition zone is present between the inflamed and proximally healthy mucosa.

Approximately 3 to 6% of adults with UC have coexisting Clostridioides difficile.

Abdominal CT scans can indicate the presence of thickening of the colon lining, can provide information of the extent of involvement.

CT scan of the abdomen cannot distinguish UC from other types of colitis.

May involve the lung with a vasculitis, interstitial disease, or with an organizing pneumonia.

Treatment: involves anti-inflammatory agents that suppress the immune system.

Disease location, and severity is considered when treating UC, with primary objectives to maintain quality of life and prevent complications, such as colorectal cancer.

Treatment goals include: clinical remission induction, and preventing future flares of disease.

No known cure available (2023).

Goals of treatment: resolve, symptoms, improve quality of life, preventing and treating complications.

About 50% of patients remain in remission for months to years with medical treatments.

Approximately 20% of patients with UC at five years are hospitalized, and 7% require colectomy.

Cured by colectomy.

Commonly used conventional treatments include aminosalicylates, oral immunomodulators, and corticosteroids.

5-Aminosalicylic acid agents are the mainstay of therapy for the induction of remission in mild to moderate active ulcerative colitis and for the maintenance of remission in ulcerative colitis and possible Crohn’s disease.

5-ASA (5-aminosalicylates), free type, mesalamine (Asacol, Lialda, Pentasa, Salofalk), is enclosed within a special capsule designed to begin releasing the active drug along the small intestine and colon, 5-ASA bound to sulfapyridine (Sulfasalzine, Azulfidine), 5-ASA molecule (Olsalazine, Dipentum) or a carrier molecule (Balsalazide, Colazol) are absorbed by the lining of the colon where it inhibits the initiation and maintenance of inflammation.

Topical 5- ASA is recommended for the induction of remission of isolated proctitis.

Proctitis resistant to topical mesalamine may44benefit from topical steroids to induce remission.

5-ASAs have a response rate of 70-80% with an effect on symptoms taking up 2-4 weeks to reach its peak.

ASAs effects are dose dependent.

Sulfasalazine, is the prototype aminosalicylate, and has an antibacterial agent, sulfapyridine, and an anti-inflammatory agent, mesalamie.

Sulfasalazine is poorly absorbed in the colon and partially absorbed in the small intestine.

Sulfasalazine and mesalamine have multiple anti-inflammatory effects: inhibition of the arachidonic acid pathway, cyclooxygenase, lipooxygenase, and platelet aggregation factor systems.

Sulfasalazine and mesalamine are primarily eliminated by the kidney and adverse reactions include hypersensitivity, bone marrow suppression, pancreatitis, pneumonitis, and hemolytic anemia.

Mesalamine comes in enema and suppository forms, as well, and is useful for patients with disease limited to the lower third of the colon.

The focus of management has shifted from symptom-based treatment to symptom management and mucosal healing.

Treating to achieve mucosal healing , with resolution of inflammatory changes to increase the likelihood of sustained steroid-free remission and prevent hospitalizations and surgery is the goal.

With mildly active ulcerative proctitis it is recommended to receive rectal (PR) 5-aminosalicylate (5-ASA) therapies at a dose of 1 g/d to induce or maintain remission.

To induce remission in patients with mildly active left-sided UC:

Rectal 5-ASA enemas at a dose of at least 1 g/d are preferred over rectal steroids.

In the setting of intolerance or nonresponse to oral (PO) and PR 5-ASA at appropriate doses, use of oral budesonide multi-matrix 9 mg/d.

Patients with mildly active extensive UC are recommended to receive PO 5-ASA at a dose of at least 2 g/d to induce remission.

Patients with UC of any extent whose condition fails to respond to 5-ASA therapy are recommended to receive PO systemic corticosteroids to induce remission.

Systemic corticosteroids are not recommended to maintain remission in patients with UC.

The course of corticosteroid should be short as possible.

For moderately active UC, PO budesonide is recommended to induce remission.

For moderately to severely active UC of any extent, PO systemic corticosteroids are recommended to induce remission.

Patients who do not respond to corticosteroids should be treated with rescue therapy including infliximab, or cyclosporine and surgical intervention should be considered.

To induce remission in patients with moderately to severely active UC anti-tumor necrosis factor (TNF) therapy using adalimumab, golimumab, infliximab, vedolizumab are recommended.

Azathioprine in combination with biologic therapies is more effective than either agent alone.

When infliximab is used as induction therapy, combination therapy with a thiopurine is recommended.Vedolizumab or tofacitinib is recommended is also recommended when anti-TNF therapy has failed previously.

VARSITY trial vedolizumab was superior to adalimumab with respect to achieving clinical remission, endoscopic improvement, but not corticosteroid free clinical remission.

Ustekinumab Is more affective than placebo producing and maintaining remission in patients with moderate-severe ulcerative colitis.

Ustekinumab usage results in clinical remission at week eight at 15.6% of patients, and at week 44, 38.2% and with treatment every 12 weeks at 43.8%.

Continue anti-TNF therapy using adalimumab, golimumab, or infliximab to maintain remission after anti-TNF induction in patients with previously moderately to severely active UC.

Continue vedolizumab to maintain remission in patients with previously moderately to severely active UC now in remission after vedolizumab induction.

Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. 

Continue tofacitinib to maintain remission in patients with previously moderately to severely active UC now in remission after tofacitinib induction.

50% of patients with UC do not have a response to anti-TNF therapies or lose response over time, such that after one year clinical remissions observed in only 17-34% of patients.

Routine use of broad-spectrum antibiotics is not recommended to manage acute severe UC.

Use methylprednisolone 60 mg/d or hydrocortisone 100 mg 3 or 4 times daily to induce remission for acute severe UC

With inadequate response to intravenous corticosteroids (IVCS) by 3-5 days to acute severe UC medical rescue therapy with infliximab or cyclosporine is recommended.

When remission is achieved with infliximab treatment, maintain remission with infliximab.

Oral mesaline treatment in mild to moderate ulcerative colitis is associated with clinical response and clinical remission rates of only 60% and 29%, respectively.

5-ASA compounds may be associated with increasing diarrhea, which occurs in 5-15% of patients.

5-ASA compounds may be associated with allergic reactions in the pancreas, lungs, kidneys, skin and bone marrow.

Sulfasalazine (Azulfidine) can decrease sperm counts.

Intravenous steroids treatment of choice for acute attacks requiring hospitalization.

Corticoteroids are the next line of treatment if adequate doses of 5-ASAs fail to improve clinical symptoms.

Corticosteroids may be given orally, rectally or intravenously to control the disease process.

Corticosteroids produce response rates of 70-80% of patients within a week of administration.

Utilization of corticosteroids for long-term use is not suggested because of serious side effects, and the drugs are tapered slowly after clinical response over a number of weeks.

Corticosteroid dependence may occur.

Approximately 80% of patients with severe UC refractory to steroids will respond to cyclopsporine therapy.

Failing five-aminosalicylate therapy or who present with more moderate to severe disease are typically treated with corticosteroids followed by a transition to a steroid sparing agent with the thiopurine, antitumor necrosis factor agent, or adhesion molecule inhibitor.

While proctocolectomy can cure the disease, medical therapies or the mainstay of treatment.

Because of increased cancer rates, surveillance colonoscopies with biopsies is the standard of care for patients with chronic ulcerative colitis.

Colonoscopy for cancer surveillance in patients with UC should begin 8-10 years after the diagnosis and should be repeated every one to two years.

Restorative proctocolectomy with ileal reservoir is the operation of choice for ulcerative colitis.

Despite medical therapy approximately 15% of patients will require proctocolectomy.

About 10% of patients with severe pancolitis the distal ileum may develop inflammatory changes, referred to as backwash ileitis.

Backwash ileitis related to incompetence of the ileocecal valve with reflux of inflammatory material from the colon.

Anaerobically prepared fecal microbiota transplantation may be an effective therapy, but studies suggest outcomes with FMT compared to standard systemic immunosuppression have generally been equivalent.

Ustekinumab targets p40 sub unit shared between IL – 12 and IL – 23 and mirikizumab which targets the p19 subunit shared bewteen IL 23 have demonstrated therapeutic effect of this pathway in UC.

Tulisokibart a humanized IgG1 kappa monoclonal antibody that binds to TLIA with high affinity and specificity is more effective than placebo in inducing clinical remission, in patients with moderate to severe active ulcerative colitis.

Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderate to severe active ulcerative colitis (COMMAND study group).