Page 1047 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1010 Part seven Organ-Specific Inflammatory Disease

general, a combination of colonoscopy (with ileal intubation, if anti–TNF-α agents reliably exert long-term control of symptoms.
possible) and small bowel examination (barium small bowel In this way, they may be used for years as long as the disease is
follow-through, computed tomography [CT] or magnetic reso- responding. Currently, medically refractory inflammatory disease
nance enterography, and capsule video endoscopy) is usually may be treated with natalizumab, an anti-α 4 integrin antibody,
sufficient to demonstrate active inflammatory disease of the colon although this is being supplanted by vedolizumab, an anti-α 4 β 7
and small bowel. Endoscopically, mucosal ulceration and friability antibody inhibiting the trafficking of lymphocytes from the blood
in a patchy distribution separated by unaffected mucosa (“skip specifically into the gut lamina propria. Because of substantially
areas”) are hallmarks of the disease. Radiographically, evidence reduced concerns about a rare infectious side effect with vedoli-
of patchy bowel wall thickening, mucosal hyperemia, stricturing, zumab (progressive multifocal leukoencephalopathy has been
and penetrating complications, such as fistulae, abscesses, and associated with natalizumab), it is a more attractive antiintegrin
extraintestinal inflammatory masses involving the bowel, all therapy for IBD. An established approach to immunosuppres-
suggest Crohn disease. Histologically, although the appearance sant- and biological-naïve patients is to begin with a combination
of noncaseating granulomata is highly supportive of a diagnosis of azathioprine and infliximab, as this has been shown to be
of Crohn disease, in practice, they are not often detected by superior to either a single agent alone for inducing remission,
45
endoscopic biopsy, particularly in adults. More often evidence especially 1 year later. This “top-down” approach continues to
of chronic inflammation, such as architectural crypt distortion be studied for long-term efficacy as well as for identifying those
and basal lymphoplasmacytosis, are sought to differentiate the patients with Crohn disease with a pretreatment risk profile
inflammation from an acute, self-limiting colitis or enteritis. predicting more aggressive disease.
Other findings, such as fecal leukocytes or elevated fecal calpro- Surgery is required in cases of complications, such as
tectin, may indicate an inflammatory colitis but is not specific bleeding, pain/obstruction, and fistulae that are refractory to
for diagnosis of a chronic idiopathic IBD, such as Crohn disease medical therapy. Surgery typically involves resection limited to
or UC. In the setting of supportive findings through imaging inflamed segments of small intestine and colon; small strictures
or endoscopy, the measurement of certain serum antibodies can can be treated in situ by stricturoplasty. In addition, surgery is
further strengthen the diagnosis of Crohn disease and even help required for treatment of intestinal adenocarcinoma, which also
46
differentiate it from UC, but they should not be used by themselves complicates the chronic inflammation of the bowel. There is
43
as diagnostic tests. It has been shown that up to 68% of patients a high incidence of endoscopic and symptomatic recurrence
with Crohn disease are seropositive for antibodies targeting of inflammation by 2 years after surgery, but to date, there is
microbial antigens, such as anti–Saccharomyces cerevisiae antibody no consensus about who should routinely receive preventive
(up to 16% of patients with UC are seropositive). Additional therapy.
antimicrobial antibodies, such as anti-OmpC, anti-I2, anti-flagellin
3, X, and CBir, also develop in Crohn disease.
It goes without saying that prior to treatment, Crohn disease KeY COnCePts
may need to be differentiated from other similarly presenting Crohn Disease
conditions, including UC, chronic ischemic colitis, infectious
enteritis/colitis (amebiasis, Yersinia enterocolitica infection, • Crohn disease affects the full thickness of the bowel wall resulting
Mycobacterium tuberculosis infection), intestinal lymphoma, in fistulae and abscesses in 70% of patients by 20 years’ disease
duration.
celiac disease, diverticula-associated colitis, and radiation- • Crohn disease is a chronic, relapsing inflammation of the bowel, and
and nonsteroidal antiinflammatory drug (NSAID)–induced up to 80% of patients will require surgical treatment at some point.
enteropathy. • Several gene mutations and many genetic loci are associated with
disease risk, including NOD2 and ATG16L1, which are important in
Treatment innate immune function.
The treatment of Crohn disease includes medical and surgical • T-helper 1 (Th1) and Th17 cytokine pathways mediate disease in animal
approaches. Since there is no cure for Crohn disease, the principles models, but the hierarchy of these cytokine pathways in human disease
is still being tested by targeting strategies in clinical trials.
of therapy are to first make sure that symptoms are secondary
to the underlying idiopathic inflammation and not caused by
infectious or noninflammatory factors, such as coexisting irritable
bowel syndrome (IBS). The goal is to induce quick remission ULCERATIVE COLITIS
of symptoms and establish therapy to maintain the remission
with aggressive initial therapy commensurate with the extent UC also involves chronic idiopathic inflammation of the gut,
and activity of the disease. A traditional approach to therapy but this is limited to the mucosal layer of the colon (Fig. 75.1E).
has been to use short-term corticosteroids and mesalamine It can affect the rectum alone (ulcerative proctitis), the distal
preparations to start with in mild disease (these agents are not transverse colon to rectum (left-sided colitis), or the entire colon
useful for long-term maintenance of a clinical response), add (pancolitis). Because it lacks the transmural inflammation of
immunosuppressants (azathioprine, 6-mercaptopurine, or Crohn disease, penetrating complications, such as fistulae and
methotrexate) if symptoms persist or are moderate, and finally abscesses, are generally not features of UC. Oral and topical (per
44
start anti–TNF-α agents for recalcitrant or initially severe disease. rectum) mesalamine preparations are most often used to treat
Only corticosteroids and the anti–TNF-α agents are relied on UC, although patients also may require corticosteroids, immu-
for inducing clinical responses in short periods, within days to nosuppressants, and anti–TNF-α antibody agents to induce and
weeks. Therefore corticosteroid use may need to be prolonged maintain remission. Unlike Crohn disease, total colectomy
while immunosuppressants are begun concomitantly, since the eliminates the disease. However, there can be ongoing complica-
latter’s clinical effects may not be maximized until months later. tions of the surgery, such as pouchitis, when an ileal pouch–anal
For maintenance of remission, only immunosuppressants and anastomosis is performed. Over 40% of patients with UC require