owing to its rapid onset. A recent landmark study found that early aggressive use of
infliximab, with or without AZA, was associated with both corticosteroid-free
clinical remission and mucosal healing in patients with moderate-to-severe CD.
Newer agents have been approved. Clinical studies have suggested a roughly
equivalent symptom response between adalimumab and infliximab, and because the
former drug is also a potent TNF-α blocker, similar safety concerns and adverse
effects have been shown between the two agents.
demonstrated in the treatment of fistulating Crohn’s disease.
advantage of adalimumab is its ability to be self-administered subcutaneously by
patients. Certolizumab contains only the antibody receptor for TNF-α bound to
polyethylene glycol to increase its duration in the body. Currently, it is only approved
for both inducing and maintaining remission in CD.
available for self-administration. Infection and other adverse effects have been
reported in clinical trials that are similar to other TNF-α blockers. Two randomized
controlled trials have found that natalizumab may be beneficial for induction and
maintenance of remission of moderate-to-severe CD in a small subset of patients, but
at the increased risk of developing progressive multifocal leukoencephalopathy
(PML), a potentially fatal adverse effect.
77 Thus, natalizumab should be reserved as a
last-line agent. Furthermore, patients are required to be enrolled in a mandatory
patient registry program (TOUCH) to receive the drug and should avoid concomitant
In 2014, vedolizumab was approved for inducing
and maintaining remission of moderate-to-severe UC and CD in patients who have
failed TNF-α therapy. There were no cases of PML observed in clinical trials and
the medication does not currently require a restricted distribution program.
Certainly, the added expense and risk of using biologics earlier in this population
needs to be weighed against the possibility of longer periods of remission and
avoidance of surgery. An additional concern is reports of hepatosplenic T-cell
lymphoma in young men receiving either AZA or 6-MP with or without concomitant
infliximab, which is usually fatal.
80 An algorithm for the treatment of CD is depicted
CASE 24-2, QUESTION 3: After 4 weeks of prednisone 40 mg daily, C.J. experienced fewer symptoms of
maintaining remission of symptoms in patients with CD?
Once prednisone has induced remission of active symptomatic CD, attempts should
16 The tapering schedule is usually fairly slow (typically, a
dose reduction of 5%–10%/week), taking several weeks to months to complete.
Several studies have demonstrated that corticosteroids are ineffective in maintaining
remission in CD, and many patients continue to have active disease while receiving
therapy. However, a significant subset of patients (25%) with CD requires chronic
administration of corticosteroids to prevent recurrence of symptoms (termed steroiddependent CD).
81 Given the poor long-term adverse effect profile of steroids, many
clinicians attempt treatment with other modalities to maintain remission.
6-MERCAPTOPURINE OR AZATHIOPRINE
Both 6-MP and AZA have a major role in maintenance treatment of CD, particularly
as a steroid-sparing strategy. Recent guidelines recommend the use of 6-MP and
AZA in most relapsing cases of CD, regardless of anatomic site, and for both severe
and steroid-dependent disease. Provided patients are appropriately monitored, these
tolerated, either MTX or infliximab can be used to maintain remission.
15 The topdown strategy of starting TNF blockers earlier in the course of disease is currently
81–83 Recent findings have prompted experts to increasingly advocate
initial therapy with biologic drugs in high-risk patients with moderate-to-severe CD
(“top-down” therapy) rather than initiating after other agents have failed.
experts believe that infliximab should be used earlier in the course of relapsing
disease, especially in patients with fistulae.
In summary, C.J.’s prednisone should be tapered as suggested previously and then
discontinued if possible. As the tapering regimen is begun, C.J. should start 6-MP
120 mg (approximately 1.5 mg/kg/day) or AZA 200 mg (approximately 2.5
mg/kg/day). This is because of the long onset of effect for the latter drugs (usually 3–
6 months). C.J.’s WBC counts should be monitored regularly, and he should be
counseled regarding the signs and symptoms of severe infection (e.g., fever, sore
throat, or chills) and pancreatitis (e.g., severe epigastric pain and nausea).
6-MERCAPTOPURINE AND AZATHIOPRINE MONITORING
AZA is a prodrug that is converted to the active moiety, 6-MP, in the liver. 6-MP is
then metabolized by xanthine oxidase, hypoxanthine-guanine
phosphoribosyltransferase, or thiopurine-S-methyltransferase (TPMT). Genetic
polymorphism determines the extent of TPMT activity. In approximately 90% of
whites, TPMT activity is considered high, but the remainder of the population has
either intermediate or low TPMT activity.
83,84 These patients are predisposed to 6-
MP or AZA myelosuppression because diminished TPMT activity leads to the
metabolism of these compounds being shunted to the other enzymatic pathways.
Accumulation of the 6-thioguanine byproducts is correlated with leukopenia.
Pharmacogenomic testing to assess TPMT activity has been developed and found to
be effective in guiding therapy with AZA or 6-MP, while minimizing the incidence of
85 The CD guidelines note that no randomized controlled
trials have compared pharmacogenomic guided dosing to usual care dosing in
patients receiving AZA or 6-MP. However, the US Food and Drug Administration
recommends such testing before initiating these medications.
retrospective studies have assessed the clinical utility of measuring AZA and 6-MP
metabolites such as 6-thioguanine and 6-methylmercaptopurine.
experts have used these data to suggest a therapeutic level for these metabolites (e.g.,
6-thioguanine levels of 250–400 pmol/8 × 10
red blood cells have been considered
optimal), the CD guidelines do not recommend their routine use.
for these tests remains to be fully determined, and data in this area are rapidly
6-mercaptopurine; MTX, methotrexate;
aFor nonfistulizing Crohn’s disease adalimumab or certolizumab are
alternative options to infliximab.
In patients who have experienced neutropenia from AZA therapy, as C.J. has, the
primary treatment is to discontinue AZA. In most cases, the WBC count will
normalize over the course of several days to weeks. In extreme cases, the use of
granulocyte colony-stimulating factor may be considered. C.J. should be monitored
for signs and symptoms of infection, and the AZA should be withheld. Frequent,
conceivably daily, WBC determinations should be made until the count is greater
CASE 24-2, QUESTION 5: C.J.’s leukocyte count returned to normal after 2 weeks. Unfortunately, he
noted during the past 5 days. What other agents should be considered to maintain remission in C.J.?
A number of other immunosuppressive drugs have been examined in CD. MTX
produces and maintains remission in patients with refractory disease. Clinical
improvement or reduction in corticosteroid dosages have been observed with 15
mg/week oral MTX or 25 mg/week of intramuscular or subcutaneous MTX in
roughly 40% of patients who had active bowel disease.
toxicity was the most common reason for discontinuing treatment, but neutropenia and
liver enzyme elevations were also reported.
89 Current guidelines recommend
reserving MTX for patients who have failed or are intolerant of 6-MP or AZA. Some
experts consider MTX to be inferior to 6-MP or AZA in CD, but no comparison
studies have been published to date. Given an apparent therapeutic failure with AZA,
a reasonable approach would be a short course of corticosteroids (prednisone 40 mg
daily with a taper for 6–8 weeks) and MTX 25 mg weekly. Folic acid 1 mg daily
should be initiated in patients started with the MTX. MTX use may result in a
depletion of folate stores because of dihydrofolate reductase inhibition.
Alternatively, biologic therapy could also be considered.
CASE 24-2, QUESTION 6: C.J. has developed an enterocutaneous fistula with his latest disease
Recent guidelines recommend that antibiotics have little role in the maintenance of
remission in CD, but they may be helpful in fistulizing disease or in patients with
abscesses. Taste disturbances and peripheral neuropathy are the most commonly
reported adverse effects associated with metronidazole treatment.
Infliximab is now firmly established as an important therapy in the treatment of CD,
especially fistulizing disease. However, a number of concerns regarding this agent
must be discussed with the patient before initiation of therapy. It is an expensive
therapy (approximately $15,000/year), although it may be cost effective in CD.
Fistulizing disease seems to respond particularly well to infliximab, and its use may
89 Acute and delayed hypersensitivity reactions can occur
and are occasionally life threatening.
21 Some clinicians premedicate patients with a
combination of diphenhydramine, acetaminophen, or corticosteroids before an
infusion; however, the most effective strategy to avoid a serious reaction is to
regularly monitor vital signs during infliximab infusion and slow the rate or stop the
infusion if any symptoms develop. The majority of reactions consist of headache,
flushing, itching, and dizziness, with anaphylactic reactions rarely occurring. Also of
concern is the development of human antichimeric antibodies in some patients
receiving infliximab, which may lead to either loss of response or immunologic
Infliximab should be avoided in patients who have a serious active infection.
Because of reports that infliximab treatment may reactivate tuberculosis, all patients
considered for treatment must receive a tuberculin skin test to rule out the disease
(see Chapter 68, Tuberculosis). If this test is negative and because C.J. does not
appear to have any other contraindications, he would seem to be an appropriate
candidate for infliximab. If latent tuberculosis is found, antitubercular treatment must
be initiated before infliximab can be considered since patients with treated latent
tuberculosis still have an increased risk of active disease.
for hepatitis B (and probably hepatitis C) is reasonable owing to the number of cases
describing reactivation of these viral infections.
66 Current data concerning a link
between TNF-α blockers use and malignancy are conflicting.
of data suggests a small but real risk of developing lymphoma in CD patients using
94 Another problem commonly faced by clinicians and patients
is loss of effectiveness in patients receiving TNF-α blockers. This may occur months
or years after initiation of therapy. Common strategies to regain response may include
increasing the dose of infliximab to 10 mg/kg per dose or switching to another TNF-α
blocker. The success of these strategies is variable, and often comes with
significantly increased treatment costs.
40 A recent paper has shed light on the
possible causes of this loss of efficacy.
In 155 patients receiving infliximab, who
had declining response to the drug, both trough serum infliximab levels and human
anticlonal antibodies (HACA) were measured. The authors found that in patients with
subtherapeutic trough infliximab levels, increasing the dose of the drug was a
markers may have the potential to be routinely used to assess the effectiveness of
infliximab, but more data on this issue are needed to make such a recommendation.
at keeping him symptom free. However, after 2 years of remission, C.J. is hospitalized for an acute
ileum. Is surgery indicated at this time?
Because medical therapy of CD is often inadequate, 78% of patients with this
disease will require surgery within 20 years of symptom onset.
surgical removal of the involved bowel in CD is not a definitive form of therapy. CD
can recur even after extensive resections.
72 Various investigations have determined
that cumulative recurrence rates after surgery for this disease are as high as 80%,
depending on the surgical procedure and disease location. Therefore, multiple
operations and their attendant risks are often necessary during the life of the CD
patient. Depending on the amount and site of the bowel removed during surgery,
specific malabsorption syndromes can occur (e.g., vitamin B12 malabsorption with
removal of the terminal ileum). If an ileostomy is part of the surgical procedure, the
patient will have to undergo significant psychological adjustments. Therefore,
surgery is indicated only for specific complications that are unresponsive to medical
therapy, and it should be avoided if possible.
Irritable bowel syndrome (IBS) is one of the most common chronic, relapsing, but
benign disorders causing patients to seek medical treatment. It exerts a significant
economic burden and is responsible for considerable morbidity in Western countries.
Until recently, little was understood about the pathophysiology or etiology of this
disorder. Indeed, some controversy exists today as to whether IBS is a distinct
syndrome or a grouping of several chronic GI disorders. Still, investigators have
made strides in understanding IBS, particularly the role of the enteric nervous system
in the etiology of this disorder. As a result, new pharmacotherapeutic options are
emerging for patients experiencing this often bewildering condition.
IBS can be defined as “a functional bowel disorder characterized by abdominal
pain associated with a change of bowel habit.”
95 The incidence of IBS has been
reported to be 3% to 20% in Western countries.
It is the most common disorder
seen by gastroenterologists and is commonly seen by primary-care clinicians as
97 Prevalence rates are dependent on IBS diagnostic criteria, which have varied
over the years. A female sex predominance of about 3:1 is evident in most
96 Some studies have demonstrated a white
predominance in IBS, whereas other studies have found no such association. Many
patients with IBS never seek medical attention, and those who do tend to see their
Many of these patients also have other functional disorders, such as fibromyalgia
and interstitial cystitis; and psychiatric disorders, such as major depression and
generalized anxiety disorder. It is estimated that IBS accounts for $33 billion in
direct and indirect costs in the United States annually.
Although knowledge of the cause of IBS remains incomplete, several theories have
emerged to explain the underlying pathophysiology of this disorder. Previously, the
primary cause of IBS was believed to be psychiatric or psychosomatic. This picture
was at least partially validated by the finding that many IBS patients had psychiatric
comorbidities. Today, it is believed that factors such as psychological stress may
exacerbate the disease, but they are not the cause of IBS.
that IBS patients tend to exhibit visceral hypersensitivity to colonic stimulation or
manipulation. Although concomitant anxiety and hypervigilance undoubtedly played a
role in such observations, it is now believed that the reaction to visceral stimuli in
these patients results in the perception of abdominal pain, whereas patients without
IBS would have no symptoms. The etiology of this hypersensitivity is the focus of
intense research efforts. Theories have emerged suggesting that the activation of
silent gut nociceptors owing to ischemia or infection may lead to increased
100 Other experts propose that an increase in the excitability of
neurons in the dorsal horn of the spinal cord lead to gut hyperalgesia. An abnormality
in the processing of ascending signals from the dorsal horn may be responsible for a
lower pain threshold in IBS patients. Similarly, findings suggest that neurotransmitter
abnormalities may cause the symptoms of IBS. Of particular interest is the role of
serotonin (5-HT) in the etiology of this disorder. Greater than 95% of the body’s 5-
HT is located in the GI tract and is stored in many cells, such as enterochromaffin
cells, neurons, and smooth muscle cells. When released, this 5-HT can trigger both
GI smooth muscle contraction and relaxation, as well as mediate GI sensory
101 Different 5-HT receptor subtypes may be responsible for these differing
actions. A study examining rectal biopsy specimens in patients with IBS found
defects in 5-HT signaling, supporting the theory of neurotransmitter abnormalities.
The primary 5-HT subtypes in the GI tract are 5-HT3 and 5-HT4
that IBS patients may have higher levels of 5-HT in the colon compared with control
103 Thus, these receptors have become the target of pharmacotherapeutic
Another proposed pathological mechanism of IBS is altered colonic motility.
Diarrhea, constipation, and abdominal bloating are common features of IBS. Patients
with IBS are often categorized as having either IBS with diarrhea (IBS-D) or IBS
95 About one-half of patients with IBS report increased
symptoms postprandially, and patients with IBS-D have been shown to have an
exaggerated response to cholecystokinin after eating, leading to increased colonic
104 However, patients with IBS-C tend to have fewer colonic propulsions
postprandially. Patients in whom bloating is the primary symptom of IBS may have
gas production from poor fermentation of carbohydrates.
105 This has led investigators
to search for a link between bacterial overgrowth of the small bowel (leading to an
increase of gas production and pain and bloating symptoms) and IBS.
The pathogenesis of IBS is poorly understood, although consensus theories are
emerging. Some investigators believe that inflammation of the GI mucosa associated
with infection may be the triggering factor that results in IBS.
symptoms associated with IBS can appear in up to 30% of patients who had an
episode of bacterial gastroenteritis in the recent past lend credence to an infectious
106 Recent studies have also determined that a percentage of patients
diagnosed with IBS may in fact have small intestinal bacterial overgrowth.
Diagnosis of the latter disorder is particularly important as treatment may involve a
simple course of antibacterials. Also controversial is the possible association of a
history of physical or sexual abuse and the development of IBS.
under emotional or psychological stress will report an exacerbation of their
symptoms, but this is not surprising considering that such stressors affect non-IBS
patients’ GI function as well.
109 Familial clustering of IBS patients suggests that both
genetics and formative environments may play a role in the pathogenesis of this
110 Finally, food intolerances (e.g., lactose intolerance) may be
One of the more challenging and frustrating aspects of IBS is its lack of biochemical
or physical markers that are pathognomonic for the disorder. This lack of “objective”
criteria for diagnosis can propagate the notion that IBS is a psychological or
psychosomatic disorder. Many patients express frustration with the traditional
medical establishment and individual providers.
111 Patients and providers often want
expensive laboratory or imaging tests to rule out other diseases; however, guidelines
suggest that extensive testing in IBS patients is usually unnecessary provided that
patients are younger than 50 years and do not present with any alarm symptoms.
Abdominal pain and cramping not relieved by a bowel movement
Weight loss (significant and unexplained)
Family history of IBD or colon cancer
Nocturnal symptoms (abdominal pain and cramping which awakes the sufferer from
The presence of alarm symptoms or an unusual finding on routine examination
(e.g., thyroid abnormality) may prompt further referrals and testing. Although several
symptom-driven criteria have been published, including the different Rome
Foundation systems and the Manning criteria, it is important to realize that such
systems have rarely been validated in IBS patients and their use to confirm or
exclude the disorder is controversial.
113 This may be why previous guidelines have
focused on a simple and practical definition for IBS: abdominal pain or discomfort
that is accompanied by a change in bowel habits for at least 3 months (without alarm
114 Once IBS is diagnosed, it should be further differentiated by
predominant symptom pattern into IBS with diarrhea (IBS-D), IBS with constipation
(IBS-C), mixed IBS or alternating bowel patterns (IBS-M), or unclassified (IBSU).
115 Symptoms are not always stable and patients may change from one IBS subtype
to the next during different stages of life. Small intestinal bacterial overgrowth or
celiac sprue may be tested for in selected patients, but routine screening is not
currently recommended. Because there is no known cure for IBS, it is logical to use
these subgroups to help direct symptomatic therapy. In most cases, the primary-care
clinician can successfully manage the IBS patient using the treatment algorithm
patients with irritable bowelsyndrome without constipation. N EnglJ Med. 2011;364:22.)
There are limited data concerning the natural history of IBS. IBS is generally
considered a benign disease with a good prognosis.
116 Patients’ symptoms often wax
and wane, and, in some cases, the syndrome resolves spontaneously.
symptoms are indicative of cancer. How should the clinician respond to V.H.’s concerns?
Clinicians must reassure patients with IBS that their symptoms are real but benign.
An effective physician–patient relationship is important for improved patient
satisfaction, adherence to therapy, and symptom reduction.
should be thoroughly counseled concerning the prognosis of IBS. Many patients are
fearful that their symptoms are indicative of severe pathology such as cancer.
Reassurance and education are vital to assuage fears and to reinforce the generally
benign nature of this disorder. Involving patients at the earliest stages in their
treatment plan is vital for patient acceptance and to avoid “doctor shopping.” Further,
some patients exhibit a phenomenon known as somatization. This is defined as a
tendency to experience and communicate somatic distress in response to
psychosocial stress and is a factor in how often IBS patients seek health care for their
118 Educational sessions and psychological techniques are thought to
decrease the risk of developing somatization, but data to date are limited concerning
119 Unfortunately, psychological disorders are present in a large
segment of IBS patients. The clinician should again reinforce the notion that IBS is
not “all in the patient’s head.” However, treatment of comorbid disorders, including
the discovery of a history of physical or sexual abuse (and possible posttraumatic
stress disorder), is an important component in successfully treating IBS.
initial intervention with patients of IBS should include an interactive patient
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