Page 1049 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1012 Part seven Organ-Specific Inflammatory Disease

also become refractory and require steroid, immunosuppressant, with lymphocytosis of the colonic epithelium found in one-third
or biological therapy and even pouch removal. of patients with classic malabsorption symptoms and small-bowel
lesions of celiac disease. This may be a sequela of gluten antigen
KeY COnCePts reactivity extended to colonic epithelial responses, but it becomes
Ulcerative Colitis important to address as an independent process related to the
microscopic colitis itself if diarrhea and colonic lymphocytosis
• Ulcerative colitis is a chronic, relapsing inflammation of the colon that persist despite a GFD. Conversely, although celiac-like villus
is limited to the mucosa and is not transmural. blunting may be seen in <10% of patients with microscopic
• Animal models and human disease show the dominant cytokines to colitis, celiac serologies will not be positive, indicating that classic
be interleukin (IL)-5 and IL-13, suggesting a T-helper 2 (Th2)–like (without gluten enteropathy is not playing a role.
IL-4) inflammatory response, although IL-17 and interferon (IFN)-γ are There is no current information on the immune mechanism
also active. of microscopic colitis. Activated NF-κB is seen in the mucosa
• Although less strongly associated with genetic inheritance compared
with Crohn disease, several disease susceptibility loci have been of microscopic colitis, consistent with the general inflammatory
identified and are associated with epithelial barrier function. picture. Increased nitric oxide and prostaglandin production
• Over the course of the disease up to 40% of patients will undergo have also been measured, possibly contributing more to the
total colectomy for refractory symptoms or detection of epithelial diarrhea rather than the inflammation. Excessive transforming
dysplasia. growth factor (TGF)-β has also been measured in collagenous
colitis, consistent with its role in collagen production and fibrosis.
Interestingly, medications have been associated with microscopic
On tHe HOrIZOn colitis, including H2 blockers, proton pump inhibitors (PPIs),
Inflammatory Bowel Disease (IBD) selective serotonin reuptake inhibitors (SSRIs), and ticlopidine,
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among others. Reports also suggest that long-term use of NSAIDs
• Establishment of new therapies targeting key cytokines and signaling may induce or sustain microscopic colitis.
pathways, especially anti-SMAD7 for transforming growth factor (TGF)-β The diagnosis of microscopic colitis relies on histology. The
enhancement, JAK/STAT inhibition, and immune cell–based sine qua non for microscopic colitis is increased numbers of
treatments intraepithelial lymphocytes (>20 lymphocytes/100 epithelial cells)
• Improvement in detection of dysplasia using molecular techniques on colonic mucosal biopsy. This can be accompanied by a chronic
for better understanding of the incidence, natural history, treatment,
and prevention of colonic epithelial dysplasia and neoplasia inflammatory infiltrate in the lamina propria and, less often, a
• Refining genome-wide association studies (GWAS) using large- limited appearance of neutrophils (especially cryptitis), the latter
scale fine-mapping to identify the actual polymorphisms in coding finding suggesting that the etiology of the microscopic colitis
and noncoding regions and to better test the mechanisms of IBD may actually be related to an injurious drug effect, such as NSAID
susceptibility exposure. In collagenous colitis, a prominent subepithelial collagen
• Defining whether the dysbiosis in IBD is a cause or effect and how band ≥10 µm is seen in addition to the intraepithelial
the microbiome is influenced by genetic background and inflammatory lymphocytosis.
status
As a general treatment approach to the patient with micro-
scopic colitis, the clinician should review and eliminate suspect
concomitant medications, such as NSAIDs. Coexisting celiac
OTHER IDIOPATHIC INFLAMMATORY disease should be considered, where appropriate, and addressed
BOWEL DISEASES with gluten withdrawal. Overall the choice of treatment begins
with low-risk medications in mild or moderate disease in an
Microscopic Colitis attempt to settle on a regimen that delivers the most relief of
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Microscopic colitis is an increasingly recognized condition that symptoms with the lowest side effects. Therefore treatment
links chronic watery diarrhea with isolated intraepithelial can begin with antidiarrheals (loperamide, diphenoxylate/
lymphocytosis (lymphocytic colitis) or with increased subepithelial atropine), adding a trial of cholestyramine (bile salt malabsorption
collagen deposition (collagenous colitis). It differs from Crohn has been hypothesized to play a role in microscopic colitis) and
disease and UC because it does not display endoscopic mucosal even a trial of mesalamine. Bismuth subsalicylate has been
damage or show evidence of histological chronicity (no archi- reported to benefit a minority of patients with microscopic colitis;
tectural crypt distortion, lymphoplasmacytosis, or loss of Goblet three 262 mg tablets PO three times daily may result in long-term
cells). However, it causes significant morbidity and may require remission in some (some have reservations about the long-term
chronic immunosuppression for treatment. Although its etiology toxic effects of bismuth). In patients with initially severe symptoms
remains elusive, there are associations with autoimmune condi- or who are refractory to these first treatments, corticosteroids
tions as well as with certain drug exposures. have been very effective. In particular, oral budesonide 9 mg
The hallmark symptom of microscopic colitis is chronic, taken once per day has reliably improved diarrhea and induced
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watery, nonbloody diarrhea that is frequently accompanied by remission, a result supported by placebo-controlled studies.
marked complaints of poor quality of life. Fatigue, arthralgias, The challenge is balancing relief of symptoms with the long-term
and weight loss may also be reported. Microscopic colitis has side effects of corticosteroid use (including budesonide) in
its typical onset in the sixth and seventh decades, has a female relapsing or steroid-dependent disease. In this case, emerging
predominance, and is associated with a history of autoimmunity strategies include use of lower doses of budesonide while monitor-
especially thyroid disease, rheumatoid arthritis, and CREST ing for side effects or using steroid-sparing immunosuppressive
(calcinosis, Raynaud phenomenon, esophageal dysmotility, medications, such as azathioprine and methotrexate, for long-term
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sclerodactyly, and telangiectasia) syndrome. A connection maintenance. Reports of anti–TNF-α drugs for refractory
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between microscopic colitis and celiac disease has also be observed, microscopic colitis have been published. Occasionally, patients