Page 1048 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 75 Immunological Diseases of the Gastrointestinal Tract 1011

surgery to treat medically refractory symptoms or development function, such as GNA12 for tight junction formation, CDH
of dysplasia over their lifetime. 47 for epithelial cadherin-1, and LAMB1 for the laminin con-
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stituent of basement membranes. When specifically assaying
Presentation epithelial cells (vs whole tissue) for epigenetic markers associ-
The presentation of UC reflects the primary involvement of the ated with genomic risk loci, there is an enhanced association
rectum and extent of proximal colitis. Bloody stool and diarrhea supporting the epithelium as a primary target for dysfunction
(including nocturnal) are common symptoms, with proctitis- in UC. 54
specific complaints of rectal urgency and incomplete evacuation
also being prominent. As in Crohn disease, fever, unexplained Diagnosis
weight loss, fatigue, and anemia can accompany the GI complaints The diagnosis of UC is based on a colitis that typically involves
or be the primary presentation. Extraintestinal manifestations the rectum and adjacent proximal colonic segments in a confluent
may include arthritis, uveitis, inflammatory skin lesions, and inflammatory injury. This is best accomplished by colonoscopy
stomatitis. An interesting genetic connection exists between (ileal intubation can confirm that the inflammation is limited
UC and HLA-B27–positive spondyloarthropathy (Chapter to the colon). Biopsy specimens should contain histological
57), with 60% of patients with ankylosing spondylitis showing features of chronic inflammation, including crypt distortion,
inflammation on colonoscopy. UC is also closely associated with crypt dropout, and lymphoplasmacytosis. The presence of acute
primary sclerosing cholangitis (PSC; Chapter 76); up to 3% of inflammatory features alone (polymorphonuclear cells, crypt
UC patients develop PSC, and up to 75% of all patients with PSC abscess, and cryptitis) may also be seen but, when in isolation,
have UC. 48 these features suggest other etiologies, such as acute infectious,
With an incidence up to 20.3 cases per 100 000 person-years, drug-induced, ischemia, and toxic exposures. Although no blood
typically the diagnosis of UC is in the second or the third decade, test can be used to diagnose UC, the presence of high-titer
and there is no significant gender preference. Approximately perinuclear antineutrophil cytoplasmic antibodies (pANCAs)
6–15% of first-degree relatives of patients with UC have a can be seen in up to 70% of patients with UC; this information
history of UC, but in general, the genetic contribution to risk can help differentiate chronic indeterminate colitis when coupled
is lower than in Crohn disease. There is a higher incidence of with anti-Saccharomyces cerevisiae mannan antibodies (ASCAs;
UC in European and North American populations compared see above). At all times, acute infections from enteric pathogens,
with that in Asian and Latin American countries. The only including Clostridium difficile, should also be excluded, as these
environmental exposures linked to risk of UC are the protec- may also occur during active IBD treatment and mimic exacerba-
tive effect of tobacco use and appendectomy in the first decade tion of disease (evaluation for cytomegalovirus [CMV] infection
of life. should be performed in the setting of UC seemingly refractory
The natural history of UC shows that most patients experience to immunosuppressants). Once a diagnosis is established, eleva-
a remitting and relapsing course (60%), although some have tions in transaminases or alkaline phosphatase should prompt
prolonged remission after one episode of disease (20%), and an evaluation for PSC starting with magnetic resonance
others have chronically active symptoms refractory to medical cholangiopancreatography.
remission (20%). Total colectomy is performed to treat refractory
symptoms or development of epithelial dysplasia. Chronic Treatment
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inflammatory UC (and Crohn colitis) is accompanied by an Treatment is tailored to the extent and activity of disease.
increased incidence of colorectal cancer (18% after 30 years’ For instance, mild to moderate proctitis can respond to topical
disease duration), so much so that recurring colonoscopic surveil- corticosteroids or mesalamine alone (enemas and/or supposi-
lance for dysplasia with biopsy is recommended starting 8–10 tories). Most often with more extensive colonic involvement,
years after diagnosis. oral mesalamine is required, which can be useful for induction
and maintenance of remission. In moderate to severe disease,
Immune Pathophysiology corticosteroids may be required to induce rapid responses, whereas
UC has been characterized as a Th2-like disease because of the immunosuppressants, such as azathioprine or 6-mercaptopurine,
increased IL-5 and IL-13 production in inflamed gut tissue seen are used for remission. Anti–TNF-α agents are used to induce
in an animal model of UC, oxazolone-induced colitis, as well as fairly rapid clinical responses and remission and may also be
49
from patient specimens. In this model, not only were mucosal used as maintenance therapy. Vedolizumab has been a recent
natural killer T (NKT) cells the source of excess IL-13, but the addition to conventional therapy as well.
colitis was reversed by immunoneutralizing anti–IL-13. 50,51 When Mesalamine-based drugs are a cornerstone of therapy in UC
translated to humans, patients with UC were found to have high and are generally included in most ongoing UC medical regimens.
capacity for IL-13 production, also by type II NKT cells. It turns Whether use of mesalamine even in quiescent disease confers
out that IL-13 is a biologically plausible effector cytokine in UC chemoprotection from developing dysplasia is still being debated,
injury because it disrupts the epithelial tight junction by upregu- but because of their generally low adverse event rate and high
lating claudin-2 and has a direct toxic effect on human gut tolerance, long-term use is a reasonable choice.
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epithelial cells in vitro. However, results from a clinical trial As discussed, surgery has a definite role in treating medi-
using an anti–IL-13 antibody in UC did not show significant cally refractory disease or addressing dysplasia discovered by
treatment efficacy. 53 surveillance colonoscopy (dysplasia surveillance is done every
Data from genetic susceptibility studies in UC have provided 1–2 years after 8–10 years of disease by taking four-quadrant
less compelling examples of disease-specific mechanisms com- biopsy specimens every 10 cm). Total colectomy is performed, and
pared with those in Crohn disease, but there are associations with options include an ileal pouch–anal anastomosis or a permanent
HLA class II genes distinct from Crohn disease. Furthermore, end ileostomy. However, even the pouch can become chronically
other associated loci contain genes involved in epithelial barrier inflamed; generally antibiotic-responsive, this inflammation can