Erythema nodosum (EN) occurs in up to 15% of CD patients and 10% of UC patients. Attacks usually correlate with bowel activity; skin lesions develop after the onset of bowel symptoms, and patients frequently have concomitant active peripheral arthritis. The lesions of EN are hot, red, tender nodules measuring 1–5 cm in diameter and are found on the anterior surface of the lower legs, ankles, calves, thighs, and arms. Therapy is directed toward the underlying bowel disease.
Pyoderma gangrenosum (PG) is seen in 1–12% of UC patients and less commonly in Crohn's colitis. Although it usually presents after the diagnosis of IBD, PG may occur years before the onset of bowel symptoms, run a course independent of the bowel disease, respond poorly to colectomy, and even develop years after proctocolectomy. It is usually associated with severe disease. Lesions are commonly found on the dorsal surface of the feet and legs but may occur on the arms, chest, stoma, and even the face. PG usually begins as a pustule and then spreads concentrically to rapidly undermine healthy skin. Lesions then ulcerate, with violaceous edges surrounded by a margin of erythema. Centrally, they contain necrotic tissue with blood and exudates. Lesions may be single or multiple and grow as large as 30 cm. They are sometimes very difficult to treat and often require intravenous (IV) antibiotics, intravenous, glucocorticoids, dapsone, azathioprine, thalidomide, IV cyclosporine, or infliximab.
Other dermatologic manifestations include pyoderma vegetans, which occurs in intertriginous areas; pyostomatitis vegetans, which involves the mucous membranes; Sweet's syndrome, a neutrophilic dermatosis; and metastatic CD, a rare disorder defined by cutaneous granuloma formation. Psoriasis affects 5–10% of patients with IBD and is unrelated to bowel activity consistent with the potential shared immunogenetic basis of these diseases. Perianal skin tags are found in 75–80% of patients with CD, especially those with colon involvement. Oral mucosal lesions, seen often in CD and rarely in UC, include aphthous stomatitis and “cobblestone” lesions of the buccal mucosa.
Peripheral arthritis develops in 15–20% of IBD patients, is more common in CD, and worsens with exacerbations of bowel activity. It is asymmetric, polyarticular, and migratory and most often affects large joints of the upper and lower extremities. Treatment is directed at reducing bowel inflammation. In severe UC, colectomy frequently cures the arthritis.
Ankylosing spondylitis (AS) occurs in about 10% of IBD patients and is more common in CD than UC. About two-thirds of IBD patients with AS express the HLA-B27 antigen. The AS activity is not related to bowel activity and does not remit with glucocorticoids or colectomy. It most often affects the spine and pelvis, producing symptoms of diffuse low-back pain, buttock pain, and morning stiffness. The course is continuous and progressive, leading to permanent skeletal damage and deformity. Infliximab reduces spinal inflammation and improves functional status and quality of life.
Sacroiliitis is symmetric, occurs equally in UC and CD, is often asymptomatic, does not correlate with bowel activity, and does not always progress to AS. Other rheumatic manifestations include hypertrophic osteoarthropathy, pelvic/femoral osteomyelitis, and relapsing polychondritis.
The incidence of ocular complications in IBD patients is 1–10%. The most common are conjunctivitis, anterior uveitis/iritis, and episcleritis. Uveitis is associated with both UC and Crohn's colitis, may be found during periods of remission, and may develop in patients following bowel resection. Symptoms include ocular pain, photophobia, blurred vision, and headache. Prompt intervention, sometimes with systemic glucocorticoids, is required to prevent scarring and visual impairment. Episcleritis is a benign disorder that presents with symptoms of mild ocular burning. It occurs in 3–4% of IBD patients, more commonly in Crohn's colitis, and is treated with topical glucocorticoids.
Hepatic steatosis is detectable in about one-half of the abnormal liver biopsies from patients with CD and UC; patients usually present with hepatomegaly. Fatty liver usually results from a combination of chronic debilitating illness, malnutrition, and glucocorticoid therapy. Cholelithiasis occurs in 10–35% of CD patients with ileitis or ileal resection. Gallstone formation is caused by malabsorption of bile acids, resulting in depletion of the bile salt pool and the secretion of lithogenic bile.
Primary sclerosing cholangitis (PSC) is a disorder characterized by both intrahepatic and extrahepatic bile duct inflammation and fibrosis, frequently leading to biliary cirrhosis and hepatic failure; approximately 5% of patients with UC have PSC, but 50–75% of patients with PSC have IBD. PSC occurs less often in patients with CD. Although it can be recognized after the diagnosis of IBD, PSC can be detected earlier or even years after proctocolectomy. Consistent with this, the immunogenetic basis for PSC appears to be overlapping but distinct from UC based upon genome-wide association studies (GWAS) although both IBD and PSC are commonly pANCA positive. Most patients have no symptoms at the time of diagnosis; when symptoms are present, they consist of fatigue, jaundice, abdominal pain, fever, anorexia, and malaise. The traditional gold-standard diagnostic test is endoscopic retrograde cholangiopancreatography (ERCP), but magnetic resonance cholangiopancreatography (MRCP) is also sensitive and specific. MRCP is reasonable as an initial diagnostic test in children and can visualize irregularities, multifocal strictures, and dilatations of all levels of the biliary tree. In patients with PSC, both ERCP and MRCP demonstrate multiple bile duct strictures alternating with relatively normal segments.
The bile acid ursodeoxycholic acid (ursodiol) may reduce alkaline phosphatase and serum aminotransferase levels, but histologic improvement has been marginal. High doses (25–30 mg/kg per day) may decrease the risk of colorectal dysplasia and cancer in patients with UC and PSC. Endoscopic stenting may be palliative for cholestasis secondary to bile duct obstruction. Patients with symptomatic disease develop cirrhosis and liver failure over 5–10 years and eventually require liver transplantation. PSC patients have a 10–15% lifetime risk of developing cholangiocarcinoma and then cannot be transplanted. Patients with IBD and PSC are at increased risk of colon cancer and should be surveyed yearly by colonoscopy and biopsy.
In addition, cholangiography is normal in a small percentage of patients who have a variant of PSC known as small duct primary sclerosing cholangitis. This variant (sometimes referred to as “pericholangitis”) is probably a form of PSC involving small caliber bile ducts. It has similar biochemical and histologic features to classic PSC. It appears to have a significantly better prognosis than classic PSC, although it may evolve into classic PSC. Granulomatous hepatitis and hepatic amyloidosis are much rarer extraintestinal manifestations of IBD.
Low bone mass occurs in 3–30% of IBD patients. The risk is increased by glucocorticoids, cyclosporine, methotrexate and total parenteral nutrition (TPN). Malabsorption and inflammation mediated by IL-1, IL-6, TNF and other inflammatory mediators also contribute to low bone density. An increased incidence of hip, spine, wrist, and rib fractures has been noted: 36% in CD and 45% in UC. The absolute risk of an osteoporotic fracture is about 1% per person per year. Fracture rates, particularly in the spine and hip, were highest among the elderly (age >60). One study noted an odds ratio of vertebral fracture to be 1.72 and hip fracture 1.59. The disease severity predicted the risk of a fracture. Only 13% of IBD patients who had a fracture were on any kind of antifracture treatment. Up to 20% of bone mass can be lost per year with chronic glucocorticoid use. The effect is dosage-dependent. Budesonide may also suppress the pituitary-adrenal axis and thus carries a risk of causing osteoporosis.
Osteonecrosis is characterized by death of osteocytes and adipocytes and eventual bone collapse. The pain is aggravated by motion and swelling of the joints. It affects the hips more often than knees and shoulders, and in one series 4.3% of patients developed osteonecrosis within 6 months of starting glucocorticoids. Diagnosis is made by bone scan or MRI, and treatment consists of pain control, cord decompression, osteotomy, and joint replacement.
More common cardiopulmonary manifestations include endocarditis, myocarditis, pleuropericarditis, and interstitial lung disease. A secondary or reactive amyloidosis can occur in patients with long-standing IBD, especially in patients with CD. Amyloid material is deposited systemically and can cause diarrhea, constipation, and renal failure. The renal disease can be successfully treated with colchicine. Pancreatitis is a rare extraintestinal manifestation of IBD and results from duodenal fistulas; ampullary CD; gallstones; PSC; drugs such as 6-mercaptopurine, azathioprine, or, very rarely, 5-ASA agents; autoimmune pancreatitis; and primary CD of the pancreas.
Treatment: Inflammatory Bowel Disease Treatment
The mainstay of therapy for mild to moderate UC is sulfasalazine and the other 5-ASA agents. These agents are effective at inducing and maintaining remission in UC. They may have a limited role in inducing remission in CD but no clear role in maintenance of CD. The most convincing evidence for the use of sulfasalazine is treatment of active Crohn's disease involving the colon. Sulfasalazine was originally developed to deliver both antibacterial (sulfapyridine) and anti-inflammatory (5-ASA) therapy into the connective tissues of joints and the colonic mucosa. The molecular structure provides a convenient delivery system to the colon by allowing the intact molecule to pass through the small intestine after only partial absorption, and to be broken down in the colon by bacterial azo reductases that cleave the azo bond linking the sulfa and 5-ASA moieties. Sulfasalazine is effective treatment for mild to moderate UC, but its high rate of side effects limits its use. Although sulfasalazine is more effective at higher doses, at 6 or 8 g/d up to 30% of patients experience allergic reactions or intolerable side effects such as headache, anorexia, nausea, and vomiting that are attributable to the sulfapyridine moiety. Hypersensitivity reactions, independent of sulfapyridine levels, include rash, fever, hepatitis, agranulocytosis, hypersensitivity pneumonitis, pancreatitis, worsening of colitis, and reversible sperm abnormalities. Sulfasalazine can also impair folate absorption, and patients should be given folic acid supplements.
Newer sulfa-free aminosalicylate preparations deliver increased amounts of the pharmacologically active ingredient of sulfasalazine (5-ASA, mesalamine) to the site of active bowel disease while limiting systemic toxicity. Peroxisome proliferator activated receptor gamma; (PPAR-gamma;) may mediate 5-ASA therapeutic action by decreasing nuclear localization of NF κB. Sulfa-free aminosalicylate formulations include alternative azo-bonded carriers, 5-ASA dimers, pH-dependent tablets, delayed-release and controlled-release preparations. Each has the same efficacy as sulfasalazine when equimolar concentrations are used. Olsalazine is composed of two 5-ASA radicals linked by an azo bond, which is split in the colon by bacterial reduction, and two 5-ASA molecules are released. Olsalazine is similar in effectiveness to sulfasalazine in treating UC, but up to 17% of patients experience nonbloody diarrhea caused by increased secretion of fluid in the small bowel. Balsalazide contains an azo bond binding mesalamine to the carrier molecule 4-aminobenzoyl-β-alanine; it is effective in the colon.
Asacol is an enteric-coated form of mesalamine with the 5-ASA being released at pH >7. The disintegration of Asacol is variable, with complete breakup of the tablet occurring in many different parts of the gut ranging from the small intestine to the splenic flexure; it has increased gastric residence when taken with a meal. Pentasa is another mesalamine formulation that uses an ethylcellulose coating to allow water absorption into small beads containing the mesalamine. Water dissolves the 5-ASA, which then diffuses out of the bead into the lumen. Disintegration of the capsule occurs in the stomach. The microspheres then disperse throughout the entire tract from the small intestine through the distal colon in both fasted and fed conditions. Additional formulations of mesalamine continue to be developed. A once-a-day formulation of mesalamine [Multi-Matrix System (MMX), marketed in the United States as Lialda] is designed to release mesalamine in the colon. The MMX technology incorporates mesalamine into a lipophilic matrix within a hydrophilic matrix encapsulated in a polymer resistant to degradation at a low pH (<7) to delay release throughout the colon. The safety profile appears to be comparable to other 5-ASA formulations. A formulation containing encapsulated mesalamine granules (Apriso) was approved for use in the United States. Apriso delivers mesalamine to the terminal ileum and colon via a proprietary extended-release mechanism (Intellicor). The outer coating (Eudragit L) dissolves at a pH >6. In addition, there is a polymer matrix core that aids in sustained release throughout the colon. Since Lialda and Apriso are given once daily, an anticipated benefit is improved compliance compared with two to four daily doses required for other mesalamine preparations. Unencapsulated versions of mesalamine (Salofalk® Granu-Stix) have been in use in Europe for induction and maintenance of remission for several years.
Appropriate doses of Asacol and other 5-ASA compounds are shown in Table 295-7. Some 50–75% of patients with mild to moderate UC improve when treated with 5-ASA doses equivalent to 2 g/d of mesalamine; the dose response continues up to at least 4.8 g/d. As a general rule, 5-ASA agents act within 2–4 weeks. 5-ASA doses equivalent to 1.5–4 g/d of mesalamine maintain remission in 50–75% of patients with UC.
Table 295-7 Oral 5-ASA Preparations |Favorite Table|Download (.pdf)
Table 295-7 Oral 5-ASA Preparations
|Preparation||Formulation||Delivery||Dosing Per Day|
|Sulfasalazine (500 mg) (Azulfidine)||Sulfapyridine-5-ASA||Colon|
3–6 g (acute)
2–4 g (maintenance)
|Olsalazine (250 mg) (Dipentum)||5-ASA-5-ASA||Colon||1–3 g|
|Balsalazide (750 mg) (Colazal)||Aminobenzoyl-alanine-5-ASA||Colon||6.75–9 g|
|Mesalamine (400, 800 mg) (Asacol)||Eudragit S (pH 7)||Distal ileum-colon|
2.4–4.8 g (acute)
1.6–4.8 g (maintenance)
|Mesalamine (1.2 g) (Lialda)||MMX mesalamine (SPD476)||Ileum-colon||2.4–4.8 g|
|Mesalamine (250, 500, 1000 mg) (Pentasa)||Ethylcellulose microgranules||Stomach-colon|
2–4 g (acute)
1.5–4 g (maintenance)
|Delayed and Extended-Release|
|Mesalamine (.375 g) (Apriso)||Intellicor extended-release mechanism||Ileum-colon||1.5 g (maintenance)|
Topical mesalamine enemas are effective in mild-to-moderate distal UC. Clinical response occurs in up to 80% of UC patients with colitis distal to the splenic flexure. Combination therapy with mesalamine in both oral and enema form is more effective than either treatment alone for both distal and extensive UC. Mesalamine suppositories are effective in treating proctitis.
The majority of patients with moderate-to-severe UC benefit from oral or parenteral glucocorticoids. Prednisone is usually started at doses of 40–60 mg/d for active UC that is unresponsive to 5-ASA therapy. Parenteral glucocorticoids may be administered as hydrocortisone, 300 mg/d, or methylprednisolone, 40–60 mg/d. Topically applied glucocorticoids are also beneficial for distal colitis and may serve as an adjunct in those who have rectal involvement plus more proximal disease. Hydrocortisone enemas or foam may control active disease, although they have no proven role as maintenance therapy. These glucocorticoids are significantly absorbed from the rectum and can lead to adrenal suppression with prolonged administration. Topical 5-ASA therapy is more effective than topical steroid therapy in the treatment of distal UC.
Glucocorticoids are also effective for treatment of moderate-to-severe CD and induce a 60–70% remission rate compared to a 30% placebo response. The systemic effects of standard glucocorticoid formulations have led to the development of more potent formulations that are less well-absorbed and have increased first-pass metabolism. Controlled ileal-release budesonide has been nearly equal to prednisone for ileocolonic CD with fewer glucocorticoid side effects. Budesonide is used for 2–3 months at a dose of 9 mg/d, then tapered. Budesonide 6 mg/d is effective in reducing relapse rates at 3–6 months but not at 12 months in CD patients with a medically induced remission.
Glucocorticoids play no role in maintenance therapy in either UC or CD. Once clinical remission has been induced, they should be tapered according to the clinical activity, normally at a rate of no more than 5 mg/week. They can usually be tapered to 20 mg/d within 4–5 weeks but often take several months to be discontinued altogether. The side effects are numerous, including fluid retention, abdominal striae, fat redistribution, hyperglycemia, subcapsular cataracts, osteonecrosis, osteoporosis, myopathy, emotional disturbances, and withdrawal symptoms. Most of these side effects, aside from osteonecrosis, are related to the dose and duration of therapy.
Antibiotics have no role in the treatment of active or quiescent UC. However, pouchitis, which occurs in about a third of UC patients after colectomy and IPAA, usually responds to treatment with metronidazole and/or ciprofloxacin.
Metronidazole is effective in active inflammatory, fistulous, and perianal CD and may prevent recurrence after ileal resection. The most effective dose is 15–20 mg/kg per day in three divided doses; it is usually continued for several months. Common side effects include nausea, metallic taste, and disulfiram-like reaction. Peripheral neuropathy can occur with prolonged administration (several months) and on rare occasions is permanent despite discontinuation. Ciprofloxacin (500 mg bid) is also beneficial for inflammatory, perianal, and fistulous CD but has recently been associated with Achilles tendinitis and rupture. Both ciprofloxacin and metronidazole antibiotics can be used as first-line drugs for short periods of time in active inflammatory, fistulizing and perianal CD.
Azathioprine and 6-Mercaptopurine
Azathioprine and 6-mercaptopurine (6-MP) are purine analogues commonly employed in the management of glucocorticoid-dependent IBD. Azathioprine is rapidly absorbed and converted to 6-MP, which is then metabolized to the active end product, thioinosinic acid, an inhibitor of purine ribonucleotide synthesis and cell proliferation. These agents also inhibit the immune response. Efficacy can be seen as early as 3–4 weeks but can take up to 4–6 months. Adherence can be monitored by measuring the levels of 6-thioguanine and 6-methyl-mercaptopurine, end products of 6-MP metabolism. Azathioprine (2–3 mg/kg per day) or 6-MP (1–1.5 mg/kg per day) have been employed successfully as glucocorticoid-sparing agents in up to two-thirds of UC and CD patients previously unable to be weaned from glucocorticoids. The role of these immunomodulators as maintenance therapy in UC and CD and for treating active perianal disease and fistulas in CD appears promising. In addition, 6-MP or azathioprine is effective for postoperative prophylaxis of CD.
Although azathioprine and 6-MP are usually well tolerated, pancreatitis occurs in 3–4% of patients, typically presents within the first few weeks of therapy, and is completely reversible when the drug is stopped. Other side effects include nausea, fever, rash, and hepatitis. Bone marrow suppression (particularly leukopenia) is dose-related and often delayed, necessitating regular monitoring of the complete blood cell count (CBC). Additionally, 1 in 300 individuals lacks thiopurine methyltransferase, the enzyme responsible for drug metabolism; an additional 11% of the population are heterozygotes with intermediate enzyme activity. Both are at increased risk of toxicity because of increased accumulation of thioguanine metabolites. Although 6-thioguanine and 6-methylmercaptopurine levels can be followed to determine correct drug dosing and reduce toxicity, weight-based dosing is an acceptable alternative. CBCs and liver function tests should be monitored frequently regardless of dosing strategy. IBD patients treated with azathioprine/6-MP are at a fourfold increased risk of developing a lymphoma. This increased risk could be a result of the medications, the underlying disease, or both.
Methotrexate (MTX) inhibits dihydrofolate reductase, resulting in impaired DNA synthesis. Additional anti-inflammatory properties may be related to decreased IL-1 production. Intramuscular (IM) or subcutaneous (SC) MTX (25 mg/week) is effective in inducing remission and reducing glucocorticoid dosage; 15 mg/week is effective in maintaining remission in active CD. Potential toxicities include leukopenia and hepatic fibrosis, necessitating periodic evaluation of CBCs and liver enzymes. The role of liver biopsy in patients on long-term MTX is uncertain but is probably limited to those with increased liver enzymes. Hypersensitivity pneumonitis is a rare but serious complication of therapy.
Cyclosporine (CSA) is a lipophilic peptide with inhibitory effects on both the cellular and humoral immune systems. CSA blocks the production of IL-2 by T-helper lymphocytes. CSA binds to cyclophilin, and this complex inhibits calcineurin, a cytoplasmic phosphatase enzyme involved in the activation of T cells. CSA also indirectly inhibits B cell function by blocking helper T cells. CSA has a more rapid onset of action than 6-MP and azathioprine.
CSA is most effective when given at 2–4 mg/kg per day IV in severe UC that is refractory to IV glucocorticoids, with 82% of patients responding. CSA can be an alternative to colectomy. The long-term success of oral CSA is not as dramatic, but if patients are started on 6-MP or azathioprine at the time of hospital discharge, remission can be maintained. For the 2 mg/kg dose, levels as measured by monoclonal radioimmunoassay or by the high performance liquid chromatography assay should be maintained between 150 and 350 ng/mL.
CSA may cause significant toxicity; renal function should be monitored frequently. Hypertension, gingival hyperplasia, hypertrichosis, paresthesias, tremors, headaches, and electrolyte abnormalities are common side effects. Creatinine elevation calls for dose reduction or discontinuation. Seizures may also complicate therapy, especially if the patient is hypomagnesemic or if serum cholesterol levels are <3.1 mmol/L (<120 mg/dL). Opportunistic infections, most notably Pneumocystis carinii pneumonia, may occur with combination immunosuppressive treatment; prophylaxis should be given. Major adverse events occurred in 15% of patients in one large study including nephrotoxicity not responding to dose adjustment, serious infections, seizures, anaphylaxis, and death of two patients. This high incidence suggests that vigorous monitoring by experienced clinicians at tertiary care centers may be required.
Tacrolimus is a macrolide antibiotic with immunomodulatory properties similar to CSA. It is 100 times as potent as CSA and is not dependent on bile or mucosal integrity for absorption. These pharmacologic properties enable tacrolimus to have good oral absorption despite proximal small bowel Crohn's involvement. It has shown efficacy in children with refractory IBD and in adults with extensive involvement of the small bowel. It is also effective in adults with steroid-dependent or refractory UC and CD as well as refractory fistulizing CD.
Biologic therapy is often reserved for moderately to severely ill patients with Crohn's disease, who have failed other therapies. Patients who respond to biologic therapies enjoy an improvement in clinical symptoms, a better quality of life, less disability, fatigue and depression, and fewer surgeries and hospitalizations.
The first biologic therapy approved for Crohn's disease was infliximab, a chimeric IgG1 antibody against TNF-alpha, which is now also approved for treatment of moderately to severely active ulcerative colitis. Of active CD patients refractory to glucocorticoids, 6-MP, or 5-ASA, 65% will respond to IV infliximab (5 mg/kg); one-third will enter complete remission. The ACCENT I (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long Term Treatment Regimen) study showed that of the patients who experience an initial response, 40% of these will maintain remission for at least 1 year with repeated infusions of infliximab every 8 weeks.
Infliximab is also effective in CD patients with refractory perianal and enterocutaneous fistulas, with the ACCENT II trial showing a 68% response rate (50% reduction in fistula drainage) and a 50% complete remission rate. Reinfusion, typically every 8 weeks, is necessary to continue therapeutic benefits in many patients.
The development of antibodies to infliximab (ATI) is associated with an increased risk of infusion reactions and a decreased response to treatment. Current practice does not include giving on-demand or episodic infusions rather than periodic (every 8 weeks) infusions because patients are more likely to develop ATI. ATI are generally present when the quality of response or the response duration to infliximab infusion decreases. Decreasing the dosing intervals or increasing the dosage to 10 mg/kg may restore the efficacy of the drug.
The SONIC (Study of Biologic and Immunomodulator-Naïve Patients with Crohn's Disease) Trial compared infliximab plus azathioprine, infliximab alone and azathioprine alone in immunomodulator and biologic naïve patients with moderate-to-severe Crohn's disease. At one year, of 508 randomized patients, the infliximab plus azathioprine group exhibited a steroid-free remission rate of 46% compared with 35% (infliximab alone) and 24% (azathioprine alone). There was also increased complete mucosal healing at week 26 with the combined approach relative to either infliximab or azathioprine alone (44% vs. 30% vs. 17%). The adverse events were equal between groups.
The annual risk of lymphoma (e.g., Hodgkin's and non-Hodgkin's lymphoma) with infliximab has been estimated to be anywhere from 5:10,000 to 20:10,000. The annual risk of lymphoma in the general population is 2:10,000. Forty-eight cases of malignancy were identified by the FDA in children and adolescents with the use of TNF blockers. Etanercept and infliximab were the only TNF blockers included in the analysis. Of the 48 cases, about 50% were lymphomas. Other malignancies such as leukemia, melanoma, and solid organ tumors were reported; malignancies rarely seen in children (e.g., leiomyosarcoma, hepatic malignancies, and renal cell carcinoma) were also observed. Of note, most of these cases (88%) were receiving other immunosuppressive medications (e.g., azathioprine and methotrexate).
Hepatosplenic T cell lymphoma is a nearly universally fatal lymphoma in patients with Crohn's disease. At least 12 cases involved immunomodulators alone, and 19 cases received combination therapy. There have been three reports in patients taking adalimumab alone without an immunomodulator. Patients tend to be young and almost all male.
The FDA also reviewed 147 postmarketing reports of leukemia (including acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) and 69 cases of new-onset psoriasis (including pustular, palmoplantar) occurring in patients using TNF blockers. The FDA concluded that there is a possible association with both leukemia and new-onset psoriasis with the use of TNF blockers.
Other morbidities of infliximab include acute infusion reactions and severe serum sickness. All of the anti-TNF drugs are associated with an increased risk of infections, particularly reactivation of latent tuberculosis and opportunistic fungal infections including disseminated histoplasmosis and coccidioidomycosis. Rarely, infliximab and the other anti-TNF drugs have been associated with optic neuritis, seizures, new-onset or exacerbation of clinical symptoms, and radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis. They may exacerbate symptoms in patients with New York Heart Association functional class III/IV heart failure.
Infliximab has also shown efficacy in UC. In two large randomized, placebo-controlled trials, 37–49% of patients responded to infliximab and 22% and 20% of patients were able to maintain remission after 30 and 54 weeks, respectively. Patients received infliximab at 0, 2, and 6 weeks and then every 8 weeks until the end of the study.
Some patients losing response or not tolerating infliximab can be switched to adalimumab or certolizumab pegol. The GAIN (Gauging Infliximab Efficacy in Infliximab Non-Responders) trial evaluated patients who were previously treated with infliximab and became intolerant or who initially responded and lost response. Three-hundred and twenty-five patients were randomized to adalimumab or placebo. At 4 weeks, 21% of the adalimumab group and 7% of the placebo group were in remission. In clinical practice, this remission rate in the adalimumab group increases over time with a dose increase to 40 mg weekly instead of every other week.
Adalimumab is a recombinant human monoclonal IgG1 antibody containing only human peptide sequences and is injected subcutaneously. Adalimumab binds TNF and neutralizes its function by blocking the interaction between TNF and its cell-surface receptor. Therefore, it seems to have a similar mechanism of action to infliximab but with less immunogenicity. Adalimumab has been approved for treatment of moderate to severe CD. CHARM (Crohn's Trial of the Fully Human Adalimumab for Remission Maintenance) is an adalimumab maintenance study in patients who responded to adalimumab induction therapy. About 50% of the patients in this trial were previously treated with infliximab. Remission rates ranged from 42–48% of infliximab naïve patients at 1 year compared with remission rates of 31–34% in the patients who had previously received infliximab. Certolizumab pegol is a PEGylated form of an anti-TNF antibody administered SC once monthly. SC certolizumab pegol was effective for induction of clinical response in patients with active inflammatory CD. In the PRECISE II (The PEGylated Antibody Fragment Evaluation in Crohn's Disease) trial of maintenance therapy with certolizumab in patients who responded to certolizumab induction, the results were similar to the CHARM trial. At week 26, the subgroup of patients who were infliximab naïve had a response of 69% as compared to 44% in patients who had previously received infliximab.
At least one-third of patients do not respond to infliximab, but no published controlled trial has examined infliximab nonresponders for a response to other anti-TNF agents. If a patient does not have an initial response to any anti-TNF therapy, currently it must be considered futile to try another. Before the approval of natalizumab, the only option for this group of patients was surgery.
Integrins are expressed on the surface of leukocytes and serve as mediators of leukocyte adhesion to vascular endothelium. Alpha4 (α4) integrin along with its beta1 (β1) or beta7 (β7) subunit interact with endothelial ligands, termed adhesion molecules or vascular addressins. Interaction between α4β7 and mucosal addressin cellular adhesion molecule (MAdCAM-1) is important in lymphocyte tracking to gut mucosa. Natalizumab is a recombinant humanized immunoglobulin G4 antibody against α4 integrin that is effective in the induction and maintenance of remission in CD patients. It was approved February 2008 for the treatment of patients with CD refractory or intolerant to anti-TNF therapy. In the ENACT-2 (Evaluation of Natalizumab in Active Crohn's Disease Therapy) study, 354 patients who had a response to natalizumab in ENACT-1 were enrolled into maintenance therapy with an infusion of natalizumab or placebo every 4 weeks through week 56. Natalizumab patients were more likely to have a response (61% vs. 28% placebo) and remission 44% versus 26% placebo. However, 3 cases of progressive multifocal leukoencephalopathy (PML) associated with the JC polyoma virus in the clinical trials and 102 cases in the postmarketing setting have been reported to date. One case occurred in a patient with Crohn's disease and 104 in patients with multiple sclerosis. The annual risk of PML associated with natalizumab is approximately 1:1000. Patients and caregivers must now adhere to the TOUCH Treatment Program, which details strict criteria including no concomitant 6-MP, azathioprine or MTX, no glucocorticoids for longer than 6 months, the signing of consent forms and a monthly check by nurses for symptoms of PML.
Other therapies currently in development include monoclonal antibodies against IL-12 and IL-23. IL-12, derived from intestinal antigen presenting cells, initiates TH1 mediated inflammation. IL-23 is a cytokine composed of a unique p19 subunit together with the p40 subunit of IL-12, which is also upregulated in CD mucosa and promotes TH17 cells and inhibits T regulatory cells. Therefore, both IL-12 and IL-23 biologic activity can be inhibited by neutralizing IL-12 p40 with specific antibodies. The discovery of IL-23R as an IBD susceptibility gene strengthens the case for the use of IL-23 directed immunotherapy in IBD. Clinical trials are under way. Other promising therapies included those directed at IL-6 and the class of selective adhesion molecule inhibitors (e.g., anti-α4β7 and anti-MadCAM1 antibodies).
Dietary antigens may stimulate the mucosal immune response. Patients with active CD respond to bowel rest, along with TPN. Bowel rest and TPN are as effective as glucocorticoids at inducing remission of active CD but are not effective as maintenance therapy. Enteral nutrition in the form of elemental or peptide-based preparations is also as effective as glucocorticoids or TPN, but these diets are not palatable. Enteral diets may provide the small intestine with nutrients vital to cell growth and do not have the complications of TPN. In contrast to CD, dietary intervention does not reduce inflammation in UC. Standard medical management of UC and CD is shown in Fig. 295-10.
Medical management of IBD. 5-ASA, 5-aminosalicylic acid; CD, Crohn's disease; UC, ulcerative colitis.
Nearly one-half of patients with extensive chronic UC undergo surgery within the first 10 years of their illness. The indications for surgery are listed in Table 295-8. Morbidity is about 20% in elective, 30% for urgent, and 40% for emergency proctocolectomy. The risks are primarily hemorrhage, contamination and sepsis, and neural injury. The operation of choice is an IPAA.
Table 295-8 Indications for Surgery |Favorite Table|Download (.pdf)
Table 295-8 Indications for Surgery
|Ulcerative Colitis||Crohn's Disease|
- Intractable disease
- Fulminant disease
- Toxic megacolon
- Colonic perforation
- Massive colonic hemorrhage
- Extracolonic disease
- Colonic obstruction
- Colon cancer prophylaxis
- Colon dysplasia or cancer
- Small Intestine
- Stricture and obstruction unresponsive to medical therapy
- Massive hemorrhage
- Refractory fistula
- Colon and rectum
- Intractable disease
- Fulminant disease
- Perianal disease unresponsive to medical therapy
- Refractory fistula
- Colonic obstruction
- Cancer prophylaxis
- Colon dysplasia or cancer
Because UC is a mucosal disease, the rectal mucosa can be dissected and removed down to the dentate line of the anus or about 2 cm proximal to this landmark. The ileum is fashioned into a pouch that serves as a neorectum. This ileal pouch is then sutured circumferentially to the anus in an end-to-end fashion. If performed carefully, this operation preserves the anal sphincter and maintains continence. The overall operative morbidity is 10%, with the major complication being bowel obstruction. Pouch failure necessitating conversion to permanent ileostomy occurs in 5–10% of patients. Some inflamed rectal mucosa is usually left behind, and thus endoscopic surveillance is necessary. Primary dysplasia of the ileal mucosa of the pouch has occurred rarely.
Patients with IPAA usually have about 6–10 bowel movements a day. On validated quality-of-life indices, they report better performance in sports and sexual activities than ileostomy patients. The most frequent complication of IPAA is pouchitis in about 30–50% of patients with UC. This syndrome consists of increased stool frequency, watery stools, cramping, urgency, nocturnal leakage of stool, arthralgias, malaise, and fever. Pouch biopsies may distinguish true pouchitis from underlying CD. Although pouchitis usually responds to antibiotics, 3–5% of patients remain refractory and may require steroids, immunomodulators, anti-TNF therapy or even pouch removal. A highly concentrated probiotic preparation with four strains of Lactobacillus, three strains of Bifidobacterium, and one strain of Streptococcus salivarius can prevent the recurrence of pouchitis when taken daily.
Most patients with CD require at least one operation in their lifetime. The need for surgery is related to duration of disease and the site of involvement. Patients with small-bowel disease have an 80% chance of requiring surgery. Those with colitis alone have a 50% chance. Surgery is an option only when medical treatment has failed or complications dictate its necessity. The indications for surgery are shown in Table 295-8.
Because CD is chronic and recurrent, with no clear surgical cure, as little intestine as possible is resected. Current surgical alternatives for treatment of obstructing CD include resection of the diseased segment and strictureplasty. Surgical resection of the diseased segment is the most frequently performed operation, and in most cases primary anastomosis can be done to restore continuity. If much of the small bowel has already been resected and the strictures are short, with intervening areas of normal mucosa, strictureplasties should be done to avoid a functionally insufficient length of bowel. The strictured area of intestine is incised longitudinally and the incision sutured transversely, thus widening the narrowed area. Complications of strictureplasty include prolonged ileus, hemorrhage, fistula, abscess, leak, and restricture.
There is evidence that mesalamine, nitro-imidazole antibiotics, 6-MP/azathioprine and infliximab are all superior to placebo for the prevention of postoperative recurrence of Crohn's disease. Mesalamine is the least effective and the side effects of the nitro-imidazole antibiotics limit their use. Risk factors for early recurrence of disease include cigarette smoking, penetrating disease (internal fistulas, abscesses or other evidence of penetration through the wall of the bowel), early recurrence since a previous surgery, multiple surgeries or a young age at the time of the first surgery. Aggressive postoperative treatment with 6-MP/azathioprine or infliximab should be considered for this group of patients. It is also recommended to evaluate for endoscopic recurrence of Crohn's disease via a colonoscopy, if possible, 6 months after surgery.
A greater percentage of patients with Crohn's colitis require surgery for intractability, fulminant disease, and anorectal disease. Several alternatives are available, ranging from the use of a temporary loop ileostomy to resection of segments of diseased colon or even the entire colon and rectum. For patients with segmental involvement, segmental colon resection with primary anastomosis can be performed. In 20–25% of patients with extensive colitis, the rectum is spared sufficiently to consider rectal preservation. Most surgeons believe that an IPAA is contraindicated in CD due to the high incidence of pouch failure. A diverting colostomy may help heal severe perianal disease or rectovaginal fistulas, but disease almost always recurs with reanastomosis. These patients often require a total proctocolectomy and ileostomy.