Drs Chris Alexakis, Sonia Saxena and Richard Pollok discuss management of inflammatory bowel disease
- People with IBD are at increased risk of developing malabsorption, osteoporosis, opportunistic infections, and bowel cancer compared with the general population
- Improved communication is required between primary and secondary care, and GPs should contact their IBD-CNS; early contact may avoid the need for hospital admission
- The immunisation requirements of people with IBD are important in preventing opportunistic infections
- Pharmacological treatment for IBD should be tailored to disease activity and extent
- Patients should be monitored for adverse effects caused by medications used in the treatment of IBD
- Haemoglobin levels should be assessed regularly as anaemia commonly occurs in IBD
- Clinicians should offer dual-energy X-ray absorptiometry scans and appropriate treatment for patients with IBD at high risk of osteoporosis (as defined in British Society of Gastroenterology guidance2)
- Surveillance colonoscopy should be offered at appropriate intervals as there is a significant increase in the risk of colorectal cancer 10 years after onset of IBD.
Inflammatory bowel disease (IBD) encompasses idiopathic, chronic, and relapsing conditions that affect the alimentary tract, and includes Crohn’s disease (CD) and ulcerative colitis (UC). Presentation is variable:1,2
- ulcerative colitis affects only the colon and most commonly causes bloody diarrhoea or rectal bleeding
- Crohn’s disease can affect any part of the gastrointestinal tract, and may cause diarrhoea, abdominal pain, weight loss, and perianal problems.
In both conditions, extraintestinal manifestations are rare but include skin, joint, and eye symptoms.3 The risk of surgery 10 years after diagnosis is approximately 15% and 50% for UC and CD, respectively.4
Patients with IBD are at increased risk of malabsorption, osteoporosis, opportunistic infections, and (in the long term) bowel cancer. Furthermore, the success of treatment with immunomodulators, such as thiopurines (azathioprine and mercaptopurine), and the newer tumour necrosis factor alpha (TNF-α) inhibitors (infliximab and adalimumab) in reducing steroid dependency and risk of surgery, has resulted in wider use of these drugs.5–7Patients receiving these medications require regular monitoring for iatrogenic harms resulting from immunosuppression, as well as side-effects that may reduce compliance with medications. Several helpful guidelines exist with respect to each of the above topics and will be summarised in this review article.8–12 NICE also provides guidance on several of the issues highlighted above, in both UC and CD.13,14
A diagnosis of IBD is usually confirmed by a gastroenterologist and the patient should, ideally, receive long-term follow up in a specialised IBD clinic. GPs are, however, becoming increasingly involved in the shared care of patients with IBD, and need to be familiar with the pertinent guidance.
Integrated care and the role of the clinical nurse specialist
The results of the third round of the UK IBD audit in 2012 included a questionnaire for GPs caring for patients with IBD who had recently been admitted to hospital.15 A summary of the key findings is shown in Box 1. The report revealed that GPs often experienced difficulties in obtaining specialist advice regarding their IBD patients. In this respect, a lack of awareness regarding the existence and role of the IBD clinical nurse specialist (IBD-CNS) was also highlighted. Currently, more than 70% of hospitals in the UK have an IBD-CNS,16 and GPs are encouraged to seek their advice in the management of patients with IBD.
The role of the IBD-CNS has evolved and they are now an integral part of the IBD multidisciplinary team; in particular, they provide a telephone advice line service for GPs and patients. The IBD-CNS can offer immediate advice on investigations, treatment, and monitoring of patients in the community, and can escalate care if required. In a UK survey of young people (aged ≤29 years) with IBD, 76% reported having access to an IBD-CNS,17 and the majority reported that this was their preferred primary point of contact.
The provision of an IBD-CNS is included as an essential requirement in the UK service standards for IBD (standard A1).18
Box 1: Summary and recommendations of 2012 UK IBD audit GP questionnaire15
- More than 90% of GPs said they were confident in dealing with IBD flare-ups —but treatments used varied widely depending on the degree of specialist input
- Less than 10% of GPs involved their IBD-CNS—there is a clear need to promote the role of the IBD-CNS in the community
- Fifty percent of GPs said they did not know who to contact for advice, or that lines of communication were slow—hospitals need to provide timely correspondence and contact details
- Treatment was not initiated nor the specialist team contacted in one-third of patients who consulted their GP in the month prior to their admission
- GPs perceived that they needed more education about IBD, particularly regarding colon cancer surveillance requirements.
- IBD=inflammatory bowel disease; CNS=clinical nurse specialist
The role of faecal calprotectin testing
Faecal calprotectin is an inflammatory marker protein released by neutrophils in the gut and can act as a surrogate marker for intestinal inflammation. NICE recommends faecal calprotectin testing as an option to help differentiate between IBD and other non-inflammatory conditions (such as irritable bowel syndrome) in adult patients with intestinal symptoms, in whom cancer is not suspected.18–21 Quantitative testing is preferable and should arguably be confined to patients aged less than 40 years and whose symptoms are indicative of IBD.22,23 A cut-off threshold of 50 μg/g in appropriate patients gives a sensitivity of over 90%, but a specificity of about 75%.
The faecal calprotectin test is particularly useful for triaging both children and young adults with suspected IBD for early specialist assessment. Faecal calprotectin testing may also be useful in distinguishing functional symptoms from disease activity in patients with established IBD, although its role in the monitoring of disease activity has yet to be fully elucidated.
The use of corticosteroids, immunomodulators (including azathioprine and mercaptopurine), and more recently TNF-α inhibitors or ‘biologic agents’ (infliximab and adalimumab) in patients with IBD increases the risk of opportunistic infection. Even modest doses of steroids (>20 mg prednisolone for >2 weeks) can increase the risk and this is further increased when steroids are used in combination with other immunomodulators. 24
Infection with Clostridium difficile in patients with IBD has been identified as a risk factor for increased morbidity and mortality in colitis.25 It is usually acquired in the community independent of previous antibiotic use and should be actively excluded by testing stools for C. difficile toxin along with other gastrointestinal infections.2 Faecal testing for stool pathogens is audited regularly in the national Inflammatory Bowel Disease Audit. The European Crohn’s and Colitis Organisation (ECCO) has recently updated its guidance on the management of opportunistic infections in patients with IBD, and in particular, the immunisation requirements for this population (see Box 2).8,9 A history of previous infection and exposure to tuberculosis, chickenpox, and hepatitis B are important, especially for people being considered for immunomodulator therapy. 8,9
When travelling abroad, people who are not receiving immunomodulators should follow standard vaccination guidelines in accordance with the destination. Immunisation with live vaccines including polio, rubella, and yellow fever are contraindicated in individuals who are receiving corticosteroids, immunomodulators, or biologic agents and for 3–6 months after cessation of treatment; 8,9 alternatives to live vaccines may be considered for patients under these circumstances. It should be noted that a letter of medical exemption from yellow fever vaccination may be required to visit certain countries, but may not be universally accepted.
Box 2: ECCO-recommended vaccinations for patients with IBD8,9
Vaccinations ideally given at diagnosis*
- Hepatitis B virus (in hepatitis B surface antigen negative patients)
- VZV vaccine (in patients whose VZV serology is negative or those without a history of VZV-associated infection)
- Human papilloma virus (in females)
Vaccinations prior to and during immunomodulator therapy*
- Inactivated trivalent influenza vaccine (yearly)
- Pneumococcal vaccine (PVC13)
- Pneumococcal polysaccharide vaccine (PPSV23 with 5-year booster)
- Human papilloma virus vaccine.
Vaccinations to AVOID during immunomodulator therapy (live vaccines)
- Polio (live vaccine)
- Yellow fever
- * This list is additional to standard vaccinations recommended for the general population.
- ECCO=European Crohn’s and Colitis Organisation; IBD=inflammatory bowel disease; VZV=Varicella zoster virus
Considerations for pharmacological treatment
A detailed overview of guidance on the therapeutic management of IBD has been covered in previous Guidelines in Practicearticles.26,27 The 3rd round of the UK IBD Audit 2012 indicated that treatment was not initiated in one-third of patients who consulted their GP in the month prior to their admission (see Box 1).15 There was also marked variability in prescribing medications by GPs when confronted with a patient with IBD having a flare. As such, we have a provided a few key pointers for GPs to consider in this circumstance.
When considering initiating therapy in UC flare, both disease location and severity need to be addressed. Severity can be assessed using the Truelove and Witts’ criteria, which stratifies a flare from mild to severe.28 A severe flare is defined as six or more bloody stools with one or more of the following systemic features: temperature >37.8 °C, pulse >90 beats per minute, anaemia, or erythrocyte sedimentation rate (ESR) >30mm/hour.
In mild-to-moderate acute flare-ups of left-sided UC or pan-ulcerative colitis, high-dose oral mesalazine medications (2.4–4.8g daily) plus topical 5-aminosalicylic acid (5-ASA) therapies are advocated by the British Society of Gastroenterology (BSG) as first-line therapy. 2 Topical therapies should be tailored to the extent of disease and may be used alone in left-sided disease: suppositories for proctitis; foam enema for distal procto-sigmoiditis; and liquid enema for more extensive left-sided colitis.2Topical therapy can also speed recovery in more extensive disease as an adjunct to treatment with oral 5-aminosalicylic acids (5-ASAs). Budesonide, a synthetic oral steroid, with low systemic absorption, should be used in moderately active ileal or ileo-caecal CD as first-line therapy.29Failure of first-line therapy should trigger immediate contact with specialist services, ideally via the IBD-CNS. Based on the associated risk of osteoporosis and the lack of evidence that they alter the long-term natural history of IBD, steroids should only be initiated after careful consideration, and usually after oral 5-ASAs and topical therapy have been tried. Topical corticosteroids are inferior to 5-ASAs and should not be used as first-line therapy. It is important to emphasise that corticosteroids have no role in maintaining remission.2,14Failure>
Monitoring drugs in primary care
The service standards for IBD encourage the development of shared-care protocols to support the prescription and monitoring of IBD drugs in general practice (service standard B1).18
One of the most frequently prescribed medications for IBD in the primary care setting are 5-ASAs, which have an excellent safety profile.30 Sulfasalazine is less commonly used now; it has a higher incidence of side-effects compared with other 5-ASAs, and male patients should be warned of potential oligospermia, an effect that is dose related 2 but reversible. Mesalazine intolerance can affect up to 15% of patients with side-effects that may lead to poor compliance, including headache, abdominal discomfort, diarrhoea, nausea, rash, and alopecia.2 Secondary renal impairment, although rare, can occur, particularly in patients with pre-existing kidney disease, and may be irreversible. The BSG guideline advocates annual monitoring of creatinine in patients on maintenance therapy, and withdrawal if there is a significant decline in renal function.2
Thiopurines, in the form of azathioprine and 6-mercaptopurine, are established steroid-sparing therapies for the long-term management of IBD, and are used in up to 60% of patients. Up to one-quarter of patients taking thiopurines report side-effects, particularly fatigue and nausea, with withdrawal rates of up to 20%. 31 Myelosuppression, pancreatitis, and liver function abnormalities are uncommon but significant. In secondary care, thiopurine methyl-transferase (TPMT) activity is measured routinely before initiation of thiopurines as this enzyme has an important role in the metabolism of thiopurines. One in 300 patients lacks TPMT activity, and is at very high risk of myelotoxicity. It is important to recognise, however, that myelotoxicity can occur with normal TPMT activity. Two-thirds of patients who develop neutropenia do so within 4 months of therapy being initiated.32
The BSG guideline suggests performing a full blood count (FBC) every 2–4 weeks for the first 2 months, then every 4–8 weeks, along with liver and renal function tests. 2 Box 3 summarises NICE guidance on monitoring patients who are taking thiopurines.33
Box 3: Summary of NICE guidance on monitoring patients of azathioprine32*
- ALT=alanine transaminase; ULN=upper limit of normal; eGFR=estimated glomerular filtration rate; FBC=full blood count
- * Although the NICE guidance is specific to azathioprine, it is not unreasonable to consider it transferable to 6-mercaptopurine.
Anaemia commonly occurs in IBD. Although usually multifactorial, the most frequent causes are iron deficiency anaemia (IDA) and anaemia of chronic disease. The severity of anaemia is often proportional to disease activity. The ECCO guideline advocates 6–12 monthly monitoring of haemoglobin (Hb) levels in stable or mild disease10,29 and more frequent monitoring in active disease.
Haemoglobin levels should be checked in combination with serum ferritin level, transferrin saturation, and C-reactive protein (CRP). Ferritin is an acute-phase reactant that may be raised in active disease, indicating normal iron status in people who are actually deficient.10 In the absence of inflammation (clinical signs or raised CRP), a ferritin level of <30 μg/L and/or transferrin saturation <16% confirms iron deficiency. In the presence of active disease, the cut-off value for ferritin should be increased to 100 μg/L.10
Confirmed IDA should always be treated. This requires appropriate control of the underlying disease activity, coupled with iron replacement therapy. This can be in the form of oral iron supplementation: a small dose of ferrous sulphate 200 mg, once or twice daily (or any other oral iron preparation) is recommended as gastrointestinal side-effects are dose related and higher doses are not absorbed. Alternatively, parenteral iron preparations, which are administered in hospital, may be used if oral preparations are not tolerated or poorly absorbed. Parenteral iron is indicated in the presence of severe anaemia (Hb <10 g/L).
In patients with small bowel Crohn’s disease and/ or extensive small bowel resections, yearly vitamin B12 and folate levels are recommended. Deficiencies of folate and B12 can be managed with oral and intramuscular preparations respectively.
Osteoporosis affects up to 3 million people in the UK,34 and patients with CD and UC have a moderately increased risk of hip fracture (relative risk of 1.68 and 1.41, respectively).35 This may be caused by a number of factors including exposure to corticosteroids, poor nutrition, malabsorption, and a low body mass index. Diagnosis of IBD at an earlier age and a history of small intestinal resection confer additional risk.11 in patients with IBD may be overlooked as general guidance primarily focuses on an older population, and blanket dual energy X-ray absorptiometry (DEXA) scanning in patients with IBD is not currently recommended. Certain individuals with significant risk factors, however, may qualify for DEXA. The World Health Organization Fracture Risk Assessment tool (FRAX®) is widely used to calculate fracture risk, but is only applicable to patients above the age of 40 years and has not been validated for an IBD population. In the absence of a risk-scoring system specific to patients with IBD, the authors suggest a holistic approach that takes into account other risk factors for osteoporosis. The BSG guidance on investigation, management, and treatment of osteoporosis in the IBD population is summarised in Box 4.11 No specific guidelines exist for younger patients without risk factors, but a DEXA scan every 5 years would seem reasonable.
Box 4: Key points in the monitoring and treatment of osteoporosis in IBD11
- Offer a DEXA scan for all patients considered at high risk of osteoporosis, for example, those with two or more of the following (non-IBD associated osteoporotic risk factors should also be considered):
- age >70 years, body mass index <20 kg/m2, continuing active disease, weight loss >10%
- Offer a DEXA scan for any high-risk patient aged <65 years if steroid treatment >3 months is being considered:
- consider bisphosphonate therapy if T score < -1.5, or repeat DEXA yearly until treatment threshold has been reached.
- Encourage lifestyle modification:
- advise patients to increase exercise, stop smoking, avoid excessive alcohol consumption, and to eat a balanced, nutritious diet
- Ensure adequate calcium intake (1000 mg daily, or 1200 mg daily if postmenopausal woman or male aged >55 years) and treat if necessary
- Assess for and treat vitamin D deficiency
- Steroids should be used cautiously—choose budesonide over prednisolone for small bowel or caecal Crohn’s disease.
- Consider commencing bisphosphonate therapy if steroid therapy is being considered for patients aged >65 years
- Consider vitamin D and oral calcium replacement for any patient on steroids
- Prescribe oral bisphophonate therapy for patients with a:
- history of fragility fracture
- low T score and significant risk factors
- Patients who are intolerant to oral bisphosphonates should be treated with ibandronic acid (3-monthly injections), raloxifene (for postmenopausal women), subcutaneous teriparatide for 18 months, or intranasal calcitonin.
- IBD=inflammatory bowel disease; DEXA=dual-energy X-ray absorptiometry
- Adapted from British Society of Gastroenterology. Guidelines for osteoporosis in inflammatory bowel disease and coeliac disease. BSG, 2007.
Patients with UC and CD have an increased risk of colorectal cancer (CRC), the risk rising significantly after 10 years from disease onset. Surveillance colonoscopy should, therefore, be offered 10 years after diagnosis. Intervals for subsequent surveillance colonoscopy (yearly, 3-yearly, or 5-yearly) depend on disease extent, the presence of inflammatory polyps, strictures, and family history of colorectal cancer.12People with primary sclerosing cholangitis, an associated condition, have a much higher risk of CRC and require yearly colonoscopy. Surveillance is primarily directed by secondary care, but it is important for GPs to know the requirements to ensure that patients who may have ceased follow up in hospital clinics are offered colonoscopy at the appropriate time.
Knowledge and appropriate implementation of current guidelines, local pathways, and shared-care protocols, coupled with effective communication between primary and secondary care are essential for the optimal care of patients with IBD. Where available, the IBD-CNS has become a critical point of contact for the GP. Good communication supports optimal management and avoidance of hospital admissions. Although individual GPs will have few patients with IBD under their care, knowledge of contemporary guidelines relevant to primary care is essential for best practice.
written by Dr David Jenner, NHS Alliance GMS contract/PBC Lead
- Crohn’s disease and ulcerative colitis are long-term conditions that require close coordination between specialist and primary care
- Commissioners should:
- work with specialist colleagues to develop local care pathways to ensure early referral of these patients and coordinated ongoing care
- consider local shared-care arrangements for prescribing the specialist drugs or even ‘year of care’ local enhanced services to include blood monitoring and vaccinations
- Clinical commissioning groups:
- may wish to invest in specialist community IBD nurses to act as key contact points for patients, or agree local tariffs for these consultations to avoid expensive outpatient tariff charges
- should agree local formularies with secondary care for expensive ‘pass through’ drugs like anti-TNF drugs not funded by the PbR tariff
- Patient-held IBD ‘record booklets’ could be developed to encourage patients to take active involvement in their care. These booklets could record:
- key drugs and monitoring requirements
- phone helpline numbers for the specialist teams to encourage their active involvement in their care
- Tariff costs for gastroenterology outpatients: £178 (new), £101 (follow up).a awww.gov.uk/government/publications/national-tariff-payment-system-2014-to-2015
IBD=inflammatory bowel disease; TNF=tumour necrosis factor; PbR=Payment by Results
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- Lakatos P, Lakatos L, Kiss L et al. Treatment of extraintestinal manifestations in inflammatory bowel disease. Digestion 2012;86 (Suppl 1): 28–35. doi: 10.1159/000341950.
- Frolkis A, Dykeman J, Negrón M et al. Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and meta-analysis of population-based studies.Gastroenterology 2013; 145 (5): 996–1006.
- Chatu S, Subramanian V, Saxena S et al. The role of thiopurines in reducing the need for surgical resection in Crohn’s disease: a systematic review and meta-analysis. Am J Gastroenterol 2014; 109 (1): 23–34.
- Chatu S, Saxena S, Subramanian V et al. The impact of timing and duration of thiopurine treatment on first intestinal resection in Crohn’s disease: national UK populationbased study 1989–2010. Am J Gastroenterol 2014; 109 (3): 409–416.
- Chhaya V, Saxena S, Cecil E et al. The impact of timing and duration of thiopurine treatment on colectomy in ulcerative colitis: a national population-based study of incident cases between 1989–2009. Aliment Pharmacol Ther 2014; doi:10.1111/apt.13017.
- Rahier J, Ben-Horin S, Chowers Y et al. European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis 2009; 3 (2): 47–91.
- Rahier J, Magro F, Abreu C et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis 2014; 8 (6): 443–468.
- Van Assche G, Dignass A, Bokemeyer B et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 3: Special situations. J Crohns Colitis 2013; 7 (1): 1–33.
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- NICE. Crohn’s disease: management in adults, children and young people. Clinical Guideline 152. NICE, 2012. Available at: www.nice.org.uk/guidance/cg152
- Royal College of Physicians website. UK IBD audit steering group. Inflammatory bowel disease (IBD) audit round three. London, RCP 2012. www.rcplondon.ac.uk/projects/ ibdauditround3
- Royal College of Physicians. The inaugural national report of the results for the primary care questionnaire responses. Part of the UK inflammatory bowel disease audit 3rd round. London: RCP, 2012. Available at: www. rcplondon.ac.uk/projects/ibdauditround3
- Alexakis C, Davies G, Stephens J et al. Perspectives and attitudes of young patients with inflammatory bowel disease: symptoms, burden of disease and communication with their healthcare professionals.Frontline Gastroenterol 2013. doi:10.1136/ flgastro-2013-100400.
- The IBD Standards Group. Quality care: Service standards for the healthcare of people who have inflammatory bowel disease (IBD). 2009. Available at: www.bsg.org.uk/ attachments/160_IBDstandards.pdf
- NICE. Faecal calprotectin diagnostic tests for inflammatory diseases of the bowel. Diagnostics Guidance 11. NICE, 2013. Available at: www. nice.org.uk/Guidance/DG11
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- NICE website. NICE pathways. Ulcerative colitis overview. pathways.nice.org.uk/ pathways/ulcerative-colitis (accessed 2 December 2014).
- Poullis. Wandsworth Clinical Commissioning Group draft guidelines on using faecal calprotectin in primary care. Personal correspondence, 2014.
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- Toruner M, Loftus E, Harmsen W et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease.Gastroenterology 2008; 134 (4): 929–936.
- Jen M-H, Saxena S, Bottle A et al. Increased health burden associated with Clostridium difficile diarrhoea in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2011; 33 (12): 1322–1331.
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