Crohn’s disease is a chronic, inflammatory, immune disease that can involve any part of the gastrointestinal tract. Patients of all ages, with a high prevalence in young adults, usually present with diarrhea, abdominal pain and weight loss, which severely affects their work and life. Multiple aspects of care, especially primary care, can reduce recurrence, prevent long-term complications and improve quality of life.
Ian D RArnott Scholar, Gastroenterology Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK, and colleagues summarized matters of diagnosis, treatment and long-term care of Crohn’s disease in an article published in the recent BMJ 2014.
Prevalence of Crohn’s disease.
Crohn’s disease is an idiopathic, chronic relapsing immune-mediated disease whose pathogenesis is not well understood and is usually thought to be the result of a combination of environmental and susceptibility factors. Its incidence and prevalence are increasing year by year, with a systematic review suggesting prevalence rates as high as 29.3/100,000, 20.2/100,000, and 10.6/100,000 in Australia, Canada, and Northern Europe, respectively.
Crohn’s disease has a significant genetic susceptibility, with offspring at increased risk if a first-degree relative has Crohn’s disease, often at 20-40 years of age, and with no significant gender differences. Patients with Crohn’s disease have a significantly higher mortality rate than the general population, with a standardized mortality ratio as high as 1.38.
Clinical features of Crohn’s disease.
The diagnosis of Crohn’s disease is a major challenge for clinicians because of its varied and insidious clinical presentation, which varies depending on the location of the lesion, but usually includes chronic diarrhea (duration of illness greater than 4 weeks, stools with or without mucopurulent blood), abdominal pain, and weight loss; patients with the above triad of signs should first undergo hematologic testing. Patients usually have nocturnal bowel movements, suggesting the need for the next step in the workup.
Some nonspecific symptoms such as abdominal discomfort, anemia, and fever are common, and extraintestinal manifestations such as oral ulcers, necrobiosis suppurativa, and erythema nodosum suggest that the patient may have inflammatory bowel disease. Remissions and relapses of Crohn’s disease usually alternate, leading to complications such as gastrointestinal strictures and fistulas. Differential diagnosis of Crohn’s disease from irritable bowel syndrome is challenging, with the former having a prodromal period of up to 10 years.
How is Crohn’s disease diagnosed?
The diagnosis of Crohn’s disease requires a combination of clinical manifestations, laboratory, imaging, endoscopic and pathological findings. Hematologic tests that should be completed include routine blood tests, inflammatory markers and vitamin D levels. Indicators that suggest the presence of Crohn’s disease include elevated inflammatory markers (e.g., C-reactive protein, hematocrit), iron deficiency anemia and nutrient deficiencies such as vitamin B12 and folic acid. Abnormalities in these indicators can be used to differentially diagnose inflammatory bowel disease and irritable bowel syndrome. All patients with diarrhea require complete stool culture to exclude Clostridium difficile and parasitic infections.
Fecal calprotectin is a protein found in the cytoplasm of neutrophils and its presence suggests intestinal inflammation. A meta-analysis of 6 studies with 670 patients showed that the sensitivity and specificity of fecal calprotectin for the diagnosis of inflammatory bowel disease were 0.93 and 0.96, respectively. this index has the advantage of being simple and cost-effective and can be used to identify patients with suspected inflammatory bowel disease. The National Institute for Health and Care Research in the UK has recommended refinement of this indicator test in primary health facilities, but this is not usually possible.
As not every patient with Crohn’s disease has typical clinical symptoms and haematological indicators, patients with persistent clinical symptoms but not consistent with irritable bowel syndrome need to be recommended for referral. Patients with suspected Crohn’s disease should also be referred to a specialized institution for further development of ancillary tests.
In secondary care systems, colonoscopy and biopsy are needed to clarify the diagnosis of Crohn’s disease. Common endoscopic findings include discontinuous inflammation or ulceration of the colon or ileocecal region with a cobblestone appearance; characteristic histological findings include focal or patchy chronic inflammation, localized glandular fossa irregularities, and granuloma formation. In 5% of patients, it is difficult to distinguish between ulcerative colitis and Crohn’s disease, when the diagnosis of inflammatory bowel disease of undifferentiated type can be made.
Although histological evidence is desirable for the diagnosis of Crohn’s disease, there are sometimes diagnostic difficulties when accumulating the small bowel. For such patients, small bowel MRI is an option, and other tests include CT (which can identify extra-intestinal complications such as abscesses and fistulas), small bowel ultrasound, capsule endoscopy, etc. Small bowel microscopy (including double balloon small bowel microscopy) can be perfected to obtain histological evidence.
How is Crohn’s disease managed?
Crohn’s disease has a wide range of effects on the health of patients. To ensure that patients have the best possible prognosis, it is important to adopt a comprehensive approach to treatment.
Patients in the active phase have a low quality of life, requiring repeated multiple hospitalizations and undergoing multiple surgeries, resulting in a poor nutritional status. Therefore early diagnosis and regular and objective assessment of the disease is important to improve the quality of life of patients. It is important that patients have access to local medical services, such as telephone access to specialists and assessment of treatment outcomes when their condition recurs.
Clinicians should use scales, such as the Universal Screening Tool for Malnutrition, to screen Crohn’s disease patients for nutrition, such as assessing their body mass index and weight loss. People at high risk for malnutrition need to be educated by a dedicated dietitian. Patients should also be assessed for micronutrients such as vitamin B12, folic acid, iron, calcium, and vitamin D, and supplemented if deficient. Smoking cessation and immunomodulatory therapy are also effective in the treatment of Crohn’s disease, reducing the recurrence rate to 35%. Patients with Crohn’s disease should discontinue the application of nonsteroidal anti-inflammatory drugs.
Various factors such as efficacy, induction or maintenance of remission, side effects, long-term risks and the patient’s own wishes should be taken into account in the selection of the appropriate drug. People at high risk of developing severe Crohn’s disease include those with young age at first presentation (<40 years), with perianal lesions, strictures and penetrating disease (e.g., perforation, intra-abdominal abscesses, abdominal fistula tracts), with upper gastrointestinal lesions, requiring hormones for first induction of remission, and women, for whom early, combination and immunosuppressive therapy is indicated.
Treatment of Crohn’s disease.
I. Induction of remission
Crohn’s disease is characterized by recurrent remissions and relapses, with clinical symptoms depending on the site of the lesion. And the treatment of the disease depends on the severity of the clinical symptoms. Patients with poor general condition should be advised to consult a specialist and be admitted to a hospital as soon as possible, and those without systemic symptoms should consult a specialist clinic. While waiting to be seen, primary care physicians can start glucocorticosteroids after ruling out infection and taper the dosage, while assessing the condition before and after treatment. For patients with Crohn’s disease who also apply immunomodulators or anti-tumor necrosis factor agents, avoid applying hormones in primary care units as much as possible.
1. Glucocorticoids
Two randomized controlled studies have shown that glucocorticoids can induce remission rates of 60-83% in active Crohn’s disease compared to the placebo group. Guidelines recommend an initial dose of 30-40 mg prednisone or 9 mg budesonide per day, with tapering after 6-8 weeks. Hormones have short- and long-term adverse effects and therefore should not be used to maintain remission. Budesonide acts locally in the intestine and thus has fewer adverse effects. It is effective in mild to moderate patients with lesions confined to the small intestine or proximal colon, but is not effective in maintenance remission therapy.
2.Biological therapy
Compared with placebo, anti-tumor necrosis factor alpha monoclonal antibody induces remission in patients with moderate to severe Crohn’s disease (81% and 17% for infliximab and placebo, respectively, at four weeks; 35.5% and 12% for adalimumab and placebo, respectively); it is also effective in treating perianal lesions (68% and 26% for infliximab and placebo, respectively, at 12 weeks). (68% vs 26% for infliximab and placebo, respectively, at 12 weeks; 33% and 13% for adalimumab and placebo, respectively, at 56 weeks of treatment).
Early application of anti-tumour necrosis factor alpha antibodies (tapered approach) may increase the rate of induction of remission and is recommended by NICE guidelines for patients who have failed conventional immunomodulatory therapy. Anti-tumour necrosis factor alpha antibodies are recommended for use in patients with Crohn’s disease with heavy risk factors and in rapid titration.
3. Enteral nutrition guidelines
Total enteral nutrition is recommended in adult patients to improve nutritional status or can be applied in patients who refuse conventional medications. A study including six randomized controlled studies of 196 patients on total enteral nutrition showed that glucocorticoids were superior to total enteral nutrition in inducing remission (OR 0.33).
II. Maintaining remission
Once a patient has achieved remission, maintenance therapy should be considered to avoid repeated application of glucocorticoids and to reduce long-term complications of hormone application. The remission should not be judged by symptoms alone, but by clinical laboratory indicators, biochemical indicators (including fecal myoglobin) and endoscopic examination results as the main reference basis.
1.Immunomodulators
Immunomodulators used for the treatment of Crohn’s disease include purines (azathioprine, mercaptopurine) and methotrexate. These drugs are effective in maintaining remission in patients with moderate to severe and glucocorticoid-dependent Crohn’s disease. The ORs for maintenance of remission were 2.32 for azathioprine and 3.32 for mercaptopurine, and the purines were slow to act (up to 17 weeks), so hormones and anti-tumor necrosis factor drugs were often needed to induce remission.
Methotrexate is also effective in maintaining remission compared to the placebo group, but it is teratogenic and poorly tolerated, so the guidelines recommend it for patients who cannot tolerate purines, anti-TNFs, or have failed to respond to these drugs. The time of discontinuation is also controversial. Experts suggest that once a patient is in clinical remission for up to 4 years, the drug can be discontinued, but there is a possibility of relapse after discontinuation.
2.Biological therapy
Anti-tumor necrosis factor agents are effective in maintaining Crohn’s disease remission, both alone and in combination with other immunomodulators, the latter being significantly more effective than the former, with mucosal healing rates of 43.9% and 16.5%, respectively. The risk of melanocytic skin cancer and other tumors is increased with OR 3.46 and 2.82, respectively, when to discontinue antitumor necrosis factor agents compared with the use alone.
When to consider surgical treatment
The most common reason for surgical resection is failure of drug therapy, including treatment of fibrous stenosis and penetrating disease (e.g., perforation, intra-abdominal abscess, abdominal fistula formation). Among these, perianal lesions due to Crohn’s disease require surgical treatment to drain the pus on the one hand and to control the fistula tract on the other. Ileal resection is the first-line treatment for terminal ileal disease alone, although postoperative recurrence is common. Some scholars are currently working on pharmacological treatment to prevent postoperative recurrence.
The main principle of surgical treatment is to preserve sufficient bowel length to avoid short bowel syndrome and bowel failure. Stenoplasty can effectively treat intestinal strictures without surgical resection. Ileorectal anastomosis is usually not recommended because of the high recurrence rate of the proximal small bowel and the potential for anatomic fistula.
Things to keep in mind during the long-term care of patients with Crohn’s disease
It is important to fully understand the vaccination history of Crohn’s disease patients before applying immunomodulatory therapy to them. It is important to ensure adequate titers of anti-hepatitis B surface antigen and anti-varicella zoster virus antibodies and to exclude underlying tuberculosis infection. When applying immunomodulatory therapy, hepatitis B carriers are at risk of liver failure and those with underlying Mycobacterium tuberculosis infection have the potential to cause tuberculosis activation. Live vaccine should be administered only before starting treatment.
Patients on immunomodulatory therapy are at increased risk of severe colds and streptococcal pneumoniae infections and require annual anti-cold virus vaccination and anti-streptococcal pneumoniae vaccination every five years. Patients on three immunosuppressive drugs are at increased risk of Pneumocystis carinii pneumonia and therefore require prophylactic cotrimoxazole for this group of patients.
Interaction of Crohn’s disease and pregnancy and lactation
The high prevalence of inflammatory bowel disease is in women of childbearing age, and patients should be aware of the advantages and disadvantages of treatment during pregnancy. There is no significant difference in the likelihood of disease activity between pregnant and non-pregnant women with Crohn’s disease, and disease activity during pregnancy also affects the course of the disease. If Crohn’s disease is active at the time of pregnancy, only 1 in 3 patients will achieve remission. Adverse outcomes during pregnancy are associated with disease activity, which should be controlled to reduce fetal and maternal complications.
If the mother is treated with immunosuppressive and anti-tumor necrosis factor drugs, the newborn is considered to be immunosuppressed at birth and should not be given live vaccines until at least six months after birth. Pregnant women with a history of pelvic surgery and extensive perianal lesions should be considered for cesarean section at delivery to reduce the risk of perianal sphincter injury.
Relationship between Crohn’s disease and tumors
Patients with Crohn’s disease have an increased risk of developing malignant tumors of the small intestine (IR 40.6) and colorectum (IR 1.9). Regular follow-up should begin 10 years after the diagnosis of inflammatory bowel disease, and the periodicity of follow-up should be determined by the patient’s risk stratification. Patients with Crohn’s disease combined with primary sclerosing cholangitis have the highest risk of malignancy and need to be followed up annually after diagnosis. The American Society for Endoscopy has guidelines for follow-up to detect early colorectal cancer.
Patients treated with purine drugs have a slightly increased risk of non-melanotic skin cancer and B-cell lymphoma and should be followed up in a dermatology department with protective measures such as appropriate clothing and barrier creams to protect against UV light and thus reduce the risk of skin cancer.
Patients treated with anti-tumor necrosis factor agents have an increased risk of developing B-cell lymphoma and rare lethal hepatosplenic T-cell lymphoma. Conversely, patients treated with purine analogs had a decreased risk of colorectal cancer. For some patients, the impact of the above scientific findings is greater, so careful consideration is needed when deciding which treatment option to pursue.
Osteoporosis
Patients with Crohn’s disease are at risk for osteoporosis due to intermittent hormone use and poor nutrient absorption. Calcium and vitamin D supplementation during hormone therapy is beneficial. The British Gastroenterological Association has guidelines on the risk of osteoporosis, including recommendations for bone density scans in patients taking hormones for more than three months and dicarbonate supplementation in patients over 65 years of age with a T-score of less than 1.5.
Mental health
Depression is an independent risk factor for quality of life in patients with Crohn’s disease and is associated with poor patient prognosis. Studies have found that patients with Crohn’s disease are at significantly higher risk of depression than the control population. Patients are concerned that fecal incontinence limits their social interactions, which in turn leads to compromised quality of life. Clinicians should be fully alert to their patients’ psychological burden and provide them with psychological comfort. Patients with Crohn’s disease can be a source of comfort to each other.