Practice Guidelines
AGA Reviews the Use of Corticosteroids, Immunomodulators, and Infliximab in IBD
Guideline source: American Gastroenterological Association
Literature search described? Yes
Evidence rating system used? Yes
Published source: Gastroenterology, March 2006
Available at: http://www.gastrojournal.org/article/PIIS0016508506000734/fulltext
Inflammatory bowel disease (IBD) encompasses gastrointestinal tract disorders, including Crohn's disease and ulcerative colitis. These disorders are common, affecting almost 1 million persons in the United States and Europe. Their presentation is varied, and a number of complications can occur. To help develop a more consistent care plan, the American Gastroenterological Association Institute issued a clinical position statement on corticosteroids, immunomodulators, and infliximab (Remicade) use in managing IBD.
Corticosteroids
Corticosteroids are used for treating patients with a moderate to severe relapse of IBD. Topical agents like suppositories or foam have been used to treat proctitis, and enemas have been effective for patients with disease up to the splenic flexure. Budesonide (Rhinocort), which has limited bioavailability and is poorly absorbed, can provide therapeutic benefit with reduced toxicity in patients with ileocecal Crohn's disease.
RECOMMENDATIONS
For patients with mild to moderate IBD, ileal-release forms of budesonide can be used to treat ileal and right-sided colonic Crohn's disease; however, they are not effective in treating ulcerative colitis. Conventional corticosteroids (e.g., prednisone) typically are used only in patients with moderate to severe IBD who do not respond to other first-line treatments (e.g., mesalamine [Rowasa] for ulcerative colitis, budesonide for Crohn's disease). For distal colonic inflammation, a topical solution of hydrocortisone or budesonide is effective.
For patients with moderate to severe IBD, corticosteroids are effective in managing Crohn's disease and ulcerative colitis; however, they are not effective in treating perianal fistulas.
Hospitalization for parenteral corticosteroids is needed for patients with severe and fulminant IBD who do not respond to oral corticosteroids and for those with severe IBD with Crohn's disease or ulcerative colitis.
Conventional corticosteroids are not effective for use as maintenance therapy in patients with Crohn's disease or ulcerative colitis. Budesonide is effective as a maintenance therapy in patients with mild to moderate ileocecal Crohn's disease who are in short-term (three months) remission; it is not effective for long-term (one year) remission.
For the initiation of remission, a prednisone (or equivalent medication) dosage ranging from 40 to 60 mg per day or 1 mg per kg per day is effective. Induction of response can average seven to 14 days. Gradually tapering the dosage by 5 mg per week to a dose of 20 mg per day and then tapering the dosage again by 2.5 to 5.0 mg per week until the dosage is below 20 mg per day is recommended. Budesonide also can be tapered gradually from the initial dose of 9 mg to 6-mg and 3-mg doses. Budesonide suppresses the adrenocortical axis, so physicians should monitor patient symptoms and evaluate for adrenal insufficiency. If a corticosteroid dose cannot be tapered, antimetabolite or infliximab therapy is needed. If a patient does not respond to therapy with high doses of prednisone (or equivalent medication) in seven to 14 days, parenteral corticosteroids are indicated; the dosage usually ranges from 40 to 60 mg per day of methylprednisolone (Medrol) or 200 to 300 mg per day of hydrocortisone.
Patients taking corticosteroids are at an increased risk of infectious complications and should be monitored for glucose intolerance and other metabolic abnormalities. Occasional bone mineral density assessment and yearly ophthalmologic examinations also are recommended for patients on long-term (more than three months) corticosteroid therapy. Those who have taken corticosteroids in the past year have a higher risk of adrenal insufficiency; stress-dose corticosteroids may be needed if the patient undergoes surgery.
Azathioprine and 6-Mercaptopurine
Azathioprine (Imuran) and 6-mercaptopurine (6-MP; Purinethol) are immunomodulators; azathioprine is converted to 6-MP nonenzymatically. They often are used to withdraw the corticosteroids and maintain remission in corticosteroid-dependent patients who have Crohn's disease or ulcerative colitis. Some studies show that azathioprine and 6-MP are effective in reducing clinical and endoscopic postoperative recurrence of Crohn's disease.
RECOMMENDATIONS
While azathioprine and 6-MP doses are being adjusted, a complete blood count with differential should be taken at least every other week. Once the doses stabilize, a complete blood count should be performed at least once every three months for as long as it is clinically appropriate. Periodic measurement of liver-associated chemistries also is recommended. Currently, the U.S. Food and Drug Administration recommends that, to avoid adverse effects, all persons should have a thiopurine methyltransferase (TPMT) genotype or phenotype assessment before undergoing azathioprine or 6-MP therapy. Persons with intermediate or normal TPMT activity also will need frequent complete blood count measurements because of the possibility of developing myelosuppression.
Because long-term corticosteroid use is undesirable, patients who have chronic, active, corticosteroid-dependent disease (i.e., Crohn's disease or ulcerative colitis) should be treated with 2 to 3 mg per kg per day of azathioprine or 1.0 to 1.5 mg per kg per day of 6-MP. Another option would be to use infliximab or infliximab combined with antimetabolites. In an attempt to avoid future corticosteroid use, those patients who have a severe flare-up of IBD also should be considered for this treatment.
6-MP is modestly effective in decreasing postoperative recurrence in Crohn's disease; its use should be an option for patients who are at high risk of postoperative recurrence or those in whom recurrence would be harmful.
An azathioprine dosage of 2 to 3 mg per kg per day or a 6-MP dosage of 1.0 to 1.5 mg per kg per day has been shown to be effective for treating perianal and enteric fistulas.
When trying to determine medical noncompliance, it is useful to monitor thiopurine metabolites in patients using 6-MP or azathioprine. Metabolites also may be useful to help optimize dosing and monitor for toxicity.
Regardless of disease distribution, a dosage of 2 to 3 mg per kg per day of azathioprine or 1.0 to 1.5 mg per kg per day of 6-MP is effective in maintaining remission in persons with Crohn's disease and for corticosteroid dose reduction in persons with ulcerative colitis. This dosage may be effective in maintaining remission in those with ulcerative colitis; however, data are conflicting and not supported by larger well-controlled trials.
Before considering surgery or other treatments, 6-MP may be tried carefully in persons with gastrointestinal intolerance (not including fever, pancreatitis, hypersensitivity reaction) to azathioprine. Azathioprine can be tried in patients with intolerance to 6-MP.
Methotrexate
Methotrexate has been used in clinical settings for almost 50 years. It produces a more rapid response in persons with IBD than 6-MP or azathioprine, and it has been shown to have a possible role in managing Crohn's disease.
RECOMMENDATIONS
Parenteral methotrexate is used for inducing remission in persons with active Crohn's disease and for maintenance of remission in those with inactive Crohn's disease. It also can be used to initiate remission with corticosteroid withdrawal in corticosteroid-dependent patients with Crohn's disease. Currently, there is insufficient evidence to support its use for inducing or maintaining remission in persons with active ulcerative colitis.
Maintenance therapy of weekly 15- to 25-mg intramuscular injections is effective in persons with active Crohn's disease that is responsive to intramuscular methotrexate. For those with chronic active Crohn's disease, 25 mg intramuscularly per week for 16 weeks and then 15 mg per week thereafter is effective.
Regular monitoring of laboratory results, including blood counts and liver-associated chemistries, is suggested for persons treated with methotrexate. Those with persistent abnormal liver-associated test results should have a liver biopsy or discontinue treatment. Methotrexate is contraindicated in pregnancy.
Mycophenolate Mofetil
Mycophenolate mofetil (Cellcept) slows down lymphocyte proliferation by blocking the synthesis of guanosine nucleotide in T cells. It was first used in IBD as an alternate immunosuppressant for persons intolerant to azathioprine or 6-MP. However, studies have shown that mycophenolate mofetil is less effective and has a higher incidence of patient intolerance, making it difficult to justify its use at this time.
Cyclosporine
Cyclosporine (Sandimmune) has a more rapid onset of action than azathioprine, 6-MP, or methotrexate. Intravenous cyclosporine is effective in managing severe ulcerative colitis and typically works within one week. Intravenous cyclosporine also can be effective for managing fistulizing Crohn's disease, but it may have toxic effects, and the disease often flares up again with use of the oral formulation. In persons with luminal Crohn's disease, it has only been effective at higher doses, which may not justify its use.
RECOMMENDATIONS
An intravenous cyclosporine dosage of 2 to 4 mg per kg per day or a colectomy should be considered for patients with severe ulcerative colitis in whom seven to 10 days of high-dose oral or parenteral corticosteroids failed. It also can help patients with severe corticosteroid-refractory ulcerative colitis avoid surgery.
To provoke a response in persons with severe ulcerative colitis who are already receiving intravenous cyclosporine, combined use of intravenous corticosteroids is recommended. Response or remission induced by intravenous cyclosporine in persons with IBD usually requires continuing therapy with oral cyclosporine for a few months. It also requires corticosteroid dose reduction, initiation of azathioprine or 6-MP treatment, and prophylaxis against Pneumocystis carinii. Continued purine analogue use is recommended for maintenance.
Although azathioprine or 6-MP therapy is required for maintenance of remission, oral cyclosporine is effective for managing corticosteroid-refractory ulcerative colitis.
High-dose oral cyclosporine has short-term effectiveness in treating luminal Crohn's disease, whereas low-dose cyclosporine (i.e., oral and intravenous) has not been proven effective.
Intravenous cyclosporine is effective for managing fistulizing Crohn's disease and should be followed with azathioprine or 6-MP therapy for maintenance of fistula closure.
Infliximab
Infliximab is a chimeric monoclonal antibody to human tumor necrosis factor alpha that has been used in clinical practice in the United States since 1998. It is effective in managing inflammatory and fistulizing Crohn's disease that has not responded to other treatments. Recent trials have shown that infliximab also is effective in managing ulcerative colitis.
Indications for infliximab use include fistulizing Crohn's disease as well as Crohn's disease and ulcerative colitis in persons who do not respond to conventional therapy. Patients who respond to induction therapy also should receive maintenance therapy.
RECOMMENDATIONS
An initial dose of 5 mg per kg, given by intravenous infusion over two hours, with three doses at weeks 0, 2, and 6 is recommended. It should be followed by maintenance therapy every eight weeks in those persons who are responsive. A health care practitioner should supervise treatment and observe the patient for approximately one hour after treatment. In patients with Crohn's disease who initially respond to treatment and then lose responsiveness, 10 mg per kg of infliximab may be tried.
Infliximab can be used to manage moderately to severely active Crohn's disease or ulcerative colitis in persons who do not respond to adequate corticosteroid or immunosuppressive treatment. Those who respond to induction therapy should continue with maintenance therapy every eight weeks. If the patient is nonresponsive after three infusions, treatment should be discontinued. If the patient achieves remission with infliximab, any concomitant corticosteroid should be withdrawn or tapered.
Infliximab also can be used to treat fistulizing Crohn's disease in persons who are nonresponsive to conventional therapies (e.g., antibiotics, immunosuppressives); however, it should not be used in persons with hypersensitivity to infliximab or those who have active infections, demyelinating disorders, severe congestive heart failure, or current or recent malignancy. Patients should be screened for latent or active tuberculosis before receiving infliximab.
Summary
Although the use of corticosteroids, immunomodulators, and infliximab for treating IBD is supported by well-designed clinical trials, many of the data are insufficient, and additional research is needed. Physicians who use these medications should clearly understand their benefits and risks so they can provide the best possible care.
AAP Releases Guidelines on Clinical Evaluation of the Child with Mental Retardation or Developmental Delays
Guideline source: American Academy of Pediatrics
Literature search described? No
Evidence rating system used? No
Published source: Pediatrics, June 2006
Available at: http://pediatrics.aappublications.org/cgi/content/full/117/6/2304
Family physicians play a major role in the early recognition and referral of children with developmental delays or mental retardation. Once the physician has recognized a possible developmental problem, she or he can help in determining whether neurologic, audiologic, or ophthalmologic evaluations or rehabilitative services are needed. The American Academy of Pediatrics (AAP) has published guidelines on the clinical evaluation of children with developmental delays or mental retardation. The guidelines focus on the diagnostic importance of the clinical history, family history, dysmorphologic examination, neurologic examination, cytogenic studies, submicroscopic subtelomeric rearrangements, molecular genetic testing, magnetic resonance imaging and computed tomography, and metabolic studies.
Developmental delay is defined as delay in the attainment of developmental milestones at the expected ages; the term usually is reserved for children younger than five years. Mental retardation is defined as a lifelong disability and cannot be diagnosed until a child is five years or older. Identifying possible developmental delay and mental retardation is the role of the family physician.
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Selected Clinical Findings and Laboratory Abnormalities Suggesting a Metabolic Disorder |
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Once developmental delay is suspected, the family physician has the role of helping the family to understand the results of diagnostic testing and to plan for the future. When a child is diagnosed with developmental delay or mental retardation, the family often experiences feelings of loss of control, and a specific diagnosis can help restore a feeling of control. A comprehensive evaluation includes the clinical history, including prenatal and birth histories; the three-generation family history; physical and neurologic examinations to detect a specific recognizable syndrome or diagnosis (see Table); and sometimes a genetic evaluation (Figure 1).
Family History
The three-generation family history should focus on family members with mental retardation, developmental delays, psychiatric diagnoses, congenital malformations, histories of miscarriage or stillbirth, and early childhood deaths. Family history does not stand alone for the diagnosis of mental retardation.
Clinical Genetics Evaluation for Developmental Delay and Mental Retardation
Figure 1. Approach to the clinical genetics evaluation for developmental delay and mental retardation. (FISH = fluorescence in situ hybridization; MRI = magnetic resonance imaging).
Reprinted with permission from Moeschler JB, Shevell M; for the American Academy of Pediatrics Committee on Genetics. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics 2006;117:2307.
Dysmorphologic Examination
Several studies have shown that mental retardation and physical anomalies often coexist, and examination by an experienced clinical geneticist often aids in diagnosis. One study showed that 42 percent of children with developmental delay or mental retardation had three or more minor anomalies.
Neurologic Examination
The neurologic examination (i.e., physical examination focused on detecting neurologic abnormalities) is critical in the evaluation of the child with developmental delays or mental retardation. Studies have shown that 42.9 percent of patients with developmental delay or mental retardation present with neurologic abnormalities. Detection of such abnormalities may signal a need for additional follow-up (e.g., electroencephalography, neuroimaging, genetic testing, referral).
Cytogenic Studies
When the etiology of developmental delay or mental retardation is unknown, cytogenic studies should be performed. Between 9 and 36 percent of patients with mental retardation have chromosomal abnormalities. In one study, four out of 10 patients with mental retardation attributed to chromosomal abnormalities had no dysmorphologic features, emphasizing the need for cytogenic testing.
Submicroscopic Subtelomeric Rearrangements
Fluorescence in situ hybridization (FISH) techniques can examine the subtelomeric regions of each chromosome to look for abnormalities that cause mental retardation. Recent testing has suggested that subtelomeric abnormalities are second only to Down syndrome as the most common cause of mental retardation. In children with mental retardation and normal results on routine chromosome analysis, the FISH technique detects subtelomeric abnormalities in 7.4 percent.
Molecular Genetic Diagnostic Testing
When the cause of mental retardation is suspected or established clinically, molecular genetic diagnostic testing is used to determine the genetic etiology.
fragile x syndrome
Fragile X syndrome is the most common genetic cause of developmental delay and mental retardation, and it is advised that children with global developmental delay and all boys with unexplained mental retardation be tested for fragile X syndrome. Routine testing of girls is not needed unless there is increased risk of fragile X syndrome (e.g., family history).
other molecular genetic testing
Genetic testing sometimes is used to confirm a clinical diagnosis, to describe the genetic mechanism for a diagnosis, or to improve the precision of genetic counseling. Molecular genetic testing also may be considered in patients who present with atypical features of a known syndrome.
Magnetic Resonance Imaging and Computed Tomography
Malformations of the brain are known to be an important finding in patients with mental retardation, but there is not universal agreement whether imaging should be used routinely as a diagnostic tool in patients with mental retardation. MRI in a young child with developmental delay or mental retardation almost always requires sedation, and MRI leads to a diagnosis in only up to 3.9 percent of patients.
Metabolic Studies
Approximately 1 percent of cases of mental retardation are caused by inborn errors of metabolism. The need for metabolic studies should be determined by the history and examination findings. Routine metabolic screening is not required.
Not all patients will receive an etiologic diagnosis after a complete diagnostic evaluation. These patients should be reevaluated by a clinical geneticist as new diagnostic testing becomes available.
Practice Guideline Briefs
CDC Releases Survey Results on STD Counseling in Adolescents
In 2000, persons 15 to 24 years of age represented 48 percent of the 18.9 million new cases of sexually transmitted diseases (STDs), despite being only one quarter of the sexually active population. The most common sexually transmitted infection in persons younger than 24 years is human papillomavirus (HPV). To assess the risk of STDs and the education and counseling practices of health care professionals, the Centers for Disease Control and Prevention (CDC) surveyed physicians who care for adolescents. The results appear in the October 20, 2006, issue of Morbidity and Mortality Weekly Report.
The survey results found that 95 percent of health care professionals thought monogamy or limiting the number of sex partners was effective in preventing the spread of HPV, and 81 percent thought these practices were worth recommending to patients. Although 91 percent of respondents considered abstinence to be highly effective, only 45 percent said they would recommend it. Family physicians and other physicians who treat adolescents were more likely to recommend abstinence compared with other health care professionals.
Although 89 percent of those surveyed said that consistent and correct condom use would be worthwhile to recommend to their patients, only 78 percent felt that correct condom use was an effective prevention. Another 23 percent of health care professionals expected consistent condom use to be adopted for long-term use by patients, compared with 21 percent for monogamy and limiting sex partners, and 6 percent for abstinence.
Among health care professionals who treat mostly adolescents, 97 percent said they always or usually remind patients to use condoms for STD prevention; 62 percent recommend monogamy or limiting the number of sex partners; and 51 percent recommend abstinence. Ninety-three percent said they routinely provide STD-prevention education to their patients, and another 69 percent said they routinely provide education about genital HPV infection to their adult or adolescent patients who they think are sexually active.
AHRQ Evaluates Peptides as Determinants for Patients with Heart Failure
B-type natriuretic peptide (BNP) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) are markers for heart failure diagnosis, prognosis, and treatment. To further study these peptides, the Agency for Healthcare Research and Quality (AHRQ) systematically reviewed the available literature. The findings are available online at http://www.ahrq.gov/clinic/tp/bnptp.htm.
In a search of Medline, CINAHL, EMBASE, AMED, and Cochrane Central from 1989 to February 2005, a total of 72 studies showed a relationship between BNPs and a determinant. A total of 103 determinants were found, including sex, age, treatment, disease, and biochemical and physiologic measures.
Pooled sensitivity and specificity values were 92 percent and 65 percent, respectively, for NT-proBNP and 94 percent and 66 percent for BNP. There was little difference between emergency, primary care, and specialized clinical settings. Further, BNP and NT-proBNP were independent indicators of mortality and other cardiac composite end points in patients at risk of coronary artery disease (CAD), diagnosed CAD, and diagnosed heart failure.
Although some studies showed that therapy reduced NT-proBNP and BNP levels, the relationship between such changes and outcomes was limited and not consistent. Therefore, AHRQ concludes that there is insufficient evidence to determine if BNP and NT-proBNP levels show changes in response to therapy for chronic heart failure.
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