The faecal calprotectin test is highly effective in differentiating inflammatory bowel disease (IBD) from irritable bowel syndrome.
It is also an effective, non-invasive tool for monitoring disease activity during treatment for patients with known IBD.
An MBS item for general practitioners to order a faecal calprotectin test will be introduced in November 2021. A separate MBS item will allow gastroenterologists to perform a follow-up test if the initial findings are unclear.
Patients with elevated faecal calprotectin levels should be promptly referred to a gastroenterologist.
Corticosteroids are not a maintenance treatment for IBD. Patients experiencing more than 1 flare per year should be referred to their gastroenterologist for escalation of treatment.
The challenges of IBD in primary care and beyond
Early intervention and intensive monitoring are essential to achieve tight control of inflammatory bowel disease (IBD). The goals of IBD management are firstly to induce remission, and then to maintain remission, preventing disease progression and avoiding hospitalisation and surgery. This approach requires timely diagnosis and specialist referral, and effective ongoing coordinated care.
NPS MedicineWise brought together health professionals involved in the diagnosis and management of IBD for a round table discussion in May 2021.
The panel consisted of a specialist IBD gastroenterologist, a gastroenterologist and a general practitioner (GP), who each shared their perspective on some of the common challenges faced when distinguishing IBD from other bowel disorders in primary care and providing optimal care for patients with IBD.
Meet the panel
A/Prof Susan Connor
Liverpool Hospital, Sydney
Dr Michael De Gregorio St Vincent's Hospital, Melbourne
A/Prof Morton Rawlin Melbourne
Case study 1: The role of faecal calprotectin in diagnosis of IBD
This case involved a 26-year-old man who presented to his GP with a 4 week history of abdominal pain, poor appetite and fatigue. He reported 3–4 episodes of watery diarrhoea each day. The patient had no significant medical history and had not recently travelled overseas.
Clinical features suggestive of IBD
Many intestinal disorders present with similar symptoms; distinguishing patients with inflammatory bowel disease (IBD) from those presenting with irritable bowel syndrome (IBS) is important.1 It was agreed that although IBD and IBS have several symptoms in common, there are key features that distinguish IBD from IBS that are useful for GPs.
The presence of any new and persistent bowel symptoms or alarm features presented in Table 1 is highly suggestive of intestinal inflammation and warrants further investigation.
Nocturnal diarrhoea (especially if wakes patient from sleep)
High WCC, platelets, ESR, CRP
Low Hb, albumin, Fe studies
Although there were no alarm features requiring urgent referral to a gastroenterologist, it was agreed that initial investigations including blood tests and faecal calprotectin testing were warranted in this case.
The role of faecal calprotectin in diagnosis of IBD
It was highlighted that there is no single test to reliably diagnose all cases of IBD however the faecal calprotectin test is highly accurate in discriminating between IBD and IBS. This can be particularly useful in low risk patients without clinical alarm features, potentially avoiding the need for more expensive and invasive tests.
Faecal calprotectin is a neutrophil-derived protein biomarker.1 It is a highly sensitive, non-invasive marker of intestinal mucosal inflammation and has been shown to be useful for differentiating between people with and without current active inflammation in the lower intestine needing further evaluation.1,3,4
It was noted that the very high negative predictive value (100%) of the faecal calprotectin test for IBD makes it an extremely useful, non-invasive tool for differentiating IBD from non-inflammatory bowel disorders.4
A patient with a normal faecal calprotectin (less than 50 micrograms/g), in the absence of clinical alarm symptoms, can be confidently diagnosed with IBS, requiring no further testing or specialist referral (see Figure 1).4
Faecal calprotectin concentrations between 50 and 100 micrograms/g are considered borderline and patients with clinical symptoms suggestive of IBD require retesting in 2 weeks (see Figure 1).
Elevated faecal calprotectin (above 100 micrograms/g) suggests there is active inflammation within the gastrointestinal system and should trigger a referral to a gastroenterologist for further investigation (see Figure 1).
Figure 1: IBD vs IBS: Role of faecal calprotectin1
In this case, the patient’s initial faecal calprotectin test result was 90 micrograms/g. It was recommended to repeat the test in 2 weeks, which showed a result of 150 micrograms/g and warranted immediate referral to a gastroenterologist for further investigation.
The faecal calprotectin test is highly useful in differentiating IBS from IBD.4
Case study 2: First-line therapy and monitoring
This case involved a 38-year-old woman with symptoms of recurrent and nocturnal diarrhoea and rectal bleeding, fever, nausea and weight loss. Initial investigations showed a faecal calprotectin of 190 micrograms/g and the patient was referred urgently to a gastroenterologist. Following endoscopic investigation, she was diagnosed with Crohn disease. The patient was otherwise healthy and was planning a second pregnancy.
Induction of remission and the role of thiopurines
Oral corticosteroids are used to induce remission in moderate to severe active Crohn disease1,5
but it was reinforced that these are not recommended for maintenance therapy and should be slowly weaned over at least 6 weeks.
The panel discussed the role of immunomodulators in maintaining steroid-free remission, identifying thiopurines as the preferred first-line treatment for Crohn disease.5
The clinical effect delay of 2 to 3 months means these agents play a limited role in inducing remission and it was recommended to commence thiopurines at the same time as corticosteroids.1
The importance of thiopurine s-methyltransferase (TPMT) activity testing before starting treatment with thiopurines was raised. TPMT is a key enzyme in the metabolism of thiopurines and variation in TPMT activity regulates thiopurine toxicity and therapeutic efficacy. Patients with reduced TPMT activity are at high risk of developing severe myelosuppression when treated with standard doses of thiopurines, while patients with normal TPMT activity can be initiated on standard dosing.1
The increased risk of infection and cancer associated with thiopurines was discussed. Although the risks are important to be mindful of, they are still very low in comparison to the risks from uncontrolled disease, which can lead to hospitalisation, surgery and reduced quality of life. For example, the annual incidence of lymphoma in the general population is 3 in 10,000 and with immunosuppression, the annual incidence still remains very low at approximately 5 in 10,000.6-8
To minimise the risk of preventable infections, vaccinations are ideally given before initiating thiopurines, as well as checking serologies for treatable infections. In addition to assessing immunity to vaccinatable infections, it’s important to perform baseline serologies for hepatitis C, Epstein Barr and human immunodeficiency virus.9
Ensuring patients are up to date with age-appropriate cancer screening and educating them about skin cancer prevention,10 is also important, with the panel recommending a baseline skin check and annual skin checks thereafter.
Thiopurines can be used safely in pregnancy and breastfeeding under the supervision of a gastroenterologist11,12
and would be the treatment of choice for the patient in this case.
Low-dose methotrexate for Crohn disease
Low-dose methotrexate is an alternative maintenance therapy for Crohn disease, but the limited efficacy data means it is generally used for patients who are intolerant of, or have contraindications to, thiopurines.5,13,14
Subcutaneous or intramuscular methotrexate has superior efficacy compared with oral methotrexate.13,14
Low-dose methotrexate, as used in Crohn disease, is not considered chemotherapy. The panel emphasised the importance of addressing this with patients to improve adherence.
Methotrexate is teratogenic during the first trimester of pregnancy so it was reinforced that it would not be a suitable option for this patient who wants to fall pregnant. Women prescribed methotrexate should use contraception while on treatment and cease methotrexate at least 3 months before planning to conceive.
Once treatment with immunomodulators has started, the panel agreed that proactive monitoring is essential to evaluate treatment response, detect complications related to disease or treatment, and identify and treat recurrent disease early.
After starting thiopurines, each patient’s full blood count and liver function tests should be performed to detect myelosuppression and hepatotoxicity at the following intervals:
Thiopurine therapeutic drug monitoring by gastroenterologists was highlighted as an integral part of treatment. Thiopurine metabolite levels should be measured 6 weeks after starting (or dose change) and then every 6–12 months once on a stable dosing regimen.1 Levels of the active metabolite 6-thioguanine nucleotide (6-TGN), and catabolic metabolite 6-methyl-mercaptopurine (6-MMP), are used to guide dosing.
Target 6-TGN levels are associated with improved clinical efficacy and lower levels with reduced treatment efficacy. Elevated 6-MMP levels are associated with hepatotoxicity.
Allopurinol shifts metabolism of thiopurines away from 6-MMP towards 6-TGN, with a need for closer monitoring.15
Figure 2: Thiopurine metabolism
To evaluate treatment response, clinicians are recommended to use a combination of patient symptoms and bio-inflammatory markers.
Faecal calprotectin is a highly specific and sensitive test for detecting active disease, including sub-clinical disease activity, and strongly correlates with mucosal inflammation. During active disease, monitoring of faecal calprotectin was recommended every 3 months, and moving to every 6 months once in remission.1
Disease activity is assessed endoscopically and radiologically by gastroenterologists at 6–12 months of treatment to evaluate mucosal healing and deeper states of disease remission.
Once in remission, patients should be reviewed every 3 to 6 months. The use of faecal calprotectin to proactively monitor patients and detect disease relapse early was discussed. It was highlighted that faecal calprotectin levels start rising approximately 3 months before the onset of clinical symptoms.16 An elevated faecal calprotectin warrants urgent gastroenterologist review for consideration of further investigation and treatment escalation. Intestinal ultrasound, which is easily performed in an outpatient setting, was discussed as a tool to detect disease recurrence with high sensitivity and specificity, allowing treatment escalation in a timely manner.3
GPs play a critical role in health care maintenance, including:
monitoring for treatment complications
cancer: annual skin checks and age-appropriate cancer screening
infection: ensure vaccinations are up to date.
monitoring for disease complications
osteoporosis: regular bone density checks
mental health, as patients with IBD are at high risk of mental health issues
Be proactive in your approach.
Detecting disease activity using bio-inflammatory markers before symptoms develop enables early optimisation of treatment and prevents complications.
Pregnancy and IBD
It was noted that common misconceptions about IBD, pregnancy and the safety of drugs in pregnancy, leads to a high rate of voluntary childlessness. Patients should be reassured that the chance of their children having IBD is low. The key to having a successful pregnancy is to have good disease control, ideally remission, prior to conception.
IBD medication safety during pregnancy and breastfeeding was discussed, highlighting that most medications are safe to use during pregnancy, with the exceptions of allopurinol and methotrexate.11 The patient presented in this case study was recommended to see her gastroenterologist and continue the prescribed thiopurine to keep her disease under control throughout her pregnancy. Closer monitoring by her gastroenterologist will be required as pregnancy may alter thiopurine metabolism.
Case study 3: Treatment adherence and flare management
The final case presented a 49-year-old man who had been diagnosed with ulcerative colitis 2 years ago. He discontinued topical aminosalicylates (5-ASA) due to the mess associated with liquid enemas and has been taking oral mesalamine. He had a flare 6 months ago and is again experiencing worsening of symptoms with nocturnal diarrhoea, blood in his stools and a fever. The patient’s comorbidities include gout, for which he is prescribed allopurinol.
Managing a disease flare
The key steps to managing a flare of ulcerative colitis were outlined, including performing a faecal calprotectin test and excluding infection. Optimising the dose and adherence to first-line oral and rectal 5-ASA therapies is essential, as the combination of oral and rectal 5-ASAs is the most effective treatment compared to either agent alone.17,18
Exploring the barriers to adherence to topical 5-ASA treatments, and providing further education and counselling about the use of these treatments is essential for this patient.
This is the patient’s second flare in a 12-month period and it was noted that a referral to a gastroenterologist is warranted for further evaluation and treatment escalation.
Patients experiencing more than 1 flare per year should be referred to a gastroenterologist.
Diet and IBD
3 key points relating to IBD and diet were discussed:
Inducing disease remission: The lack of evidence for dietary therapy as a treatment for an IBD flare was discussed, other than for Crohn disease where Exclusive Enteral Nutrition (EEN) and the Crohn Disease Exclusion Diet (CDED) have been shown to be as effective as corticosteroids.19,20
Maintaining disease remission: A healthy well-balanced diet in line with current Australian healthy eating guidelines is recommended by the panel during remission of IBD, including high-fibre containing foods such as fruit, vegetables and wholegrains.21 A low-fibre diet may be necessary when strictures are present in Crohn disease, otherwise a healthy well-balanced diet including fibre is recommended when patients are in remission.
Avoiding malnutrition: It is important to counsel patients about food avoidance or restrictions which can lead to malnutrition. Refer patients who are reporting food-related symptoms to a dietitian, particularly an IBD dietitian if available, for further assessment.
Regular exercise, reducing alcohol intake and smoking cessation were also highlighted as important lifestyle factors that may be protective for IBD and should be addressed with this patient.
The importance of both symptoms and bio-inflammatory markers for monitoring treatment response was discussed. It was recommended that an immunomodulator should be introduced to maintain remission and reduce the need for future corticosteroids. Although the efficacy data for ulcerative colitis is not as robust as for Crohn disease, an immunomodulator increases steroid-free remission rates.18
Thiopurines are the preferred agent as there is less data about the effectiveness of methotrexate in treating ulcerative colitis.13
The patient in this case study is prescribed allopurinol for gout and it was noted that allopurinol shifts metabolism of thiopurines away from 6-MMP towards 6-TGN.15
The panel recommended introducing thiopurines at a lower dose and monitoring closely for adverse drug reactions.
The recommended treatment target in ulcerative colitis is mucosal healing, as this improves long-term remission rates and reduces the risk of colectomy. Faecal calprotectin can be used as a surrogate marker of mucosal inflammation and performed 3 months after thiopurine initiation to evaluate treatment response. Endoscopic evaluation will typically be considered from 6 months for histological evidence of mucosal healing.
If this patient’s symptoms and/or bio-inflammatory markers continued to worsen despite therapeutic levels of thiopurine metabolites, it was agreed that it is essential for a gastroenterologist to be involved for escalation of treatment to biologics and/or small molecules. The key message was to avoid prescribing recurrent courses of corticosteroids. If the patient is having more than 1 flare per year, they need to be referred to their gastroenterologist for therapy escalation.
The 3 cases presented in the roundtable discussion provide insight into best practice for management of IBD. Prompt gastroenterologist referral for patients who have bowel symptoms with alarm features or an elevated faecal calprotectin level is warranted for timely evaluation of possible IBD and early treatment initiation. For patients with an established diagnosis of IBD, regular proactive monitoring is essential to evaluate treatment response and also detect complications and identify early disease recurrence. Good coordination and communication between GPs and gastroenterologists underpins safe and high quality care for patients with IBD.
Dr Michael De Gregorio is a consultant gastroenterologist and an inflammatory bowel disease clinician-research fellow at St Vincent's Hospital, Melbourne.
In 2020 he became a fellow of the Royal Australasian College of Physicians and was awarded an Australian Commonwealth Government scholarship to undertake a PhD at the University of Melbourne. His research focuses on the optimisation of surgical and medical management in perianal fistulising Crohn's disease, with an interest in biologic drugs and therapeutic drug monitoring.
He was central in the development of a new coordinate multidisciplinary care model for patients with perianal fistulising Crohn's disease at St Vincent's.