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Gastroenterology Today Autumn 2023

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Volume 34 No. 3 <strong>Autumn</strong> <strong>2023</strong><br />

THE BEST DEFENCE IS<br />

DEFENDO<br />

DEFENDO TM sterile single use valves eliminate<br />

the need for manual cleaning and reprocessing


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CONTENTS<br />

CONTENTS<br />

<strong>Gastroenterology</strong> <strong>Today</strong><br />

4 EDITOR’S COMMENT<br />

08 FEATURE Celiac disease related liver manifestations in<br />

two case study patients<br />

This issue edited by:<br />

Aaron Bhakta<br />

c/o Media Publishing Company<br />

Greenoaks, Lockhill<br />

Upper Sapey, Worcester, WR6 6XR<br />

12 FEATURE Fatigue in patients with inflammatory bowel<br />

disease—strongly influenced by depression<br />

and not identifiable through laboratory testing:<br />

a cross-sectional survey study<br />

23 NEWS<br />

27 COMPANY NEWS<br />

ADVERTISING & CIRCULATION:<br />

Media Publishing Company<br />

Greenoaks, Lockhill<br />

Upper Sapey, Worcester, WR6 6XR<br />

Tel: 01886 853715<br />

E: info@mediapublishingcompany.com<br />

www.ambulanceukonline.com<br />

PUBLISHED DATES:<br />

March, June, September and December.<br />

COPYRIGHT:<br />

Media Publishing Company<br />

Greenoaks<br />

Lockhill<br />

Upper Sapey, Worcester, WR6 6XR<br />

COVER STORY<br />

With over 30 steps to sufficient manual cleaning and reprocessing of reusable<br />

Biopsy, Air/Water, and Suction Valves, the DEFENDO range of sterile single use<br />

valves from STERIS UK, eliminates these steps.<br />

PUBLISHERS STATEMENT:<br />

The views and opinions expressed in<br />

this issue are not necessarily those of<br />

the Publisher, the Editors or Media<br />

Publishing Company<br />

Next Issue <strong>Autumn</strong> <strong>2023</strong><br />

DEFENDO Valves are high-performance, high-quality products that support<br />

procedural control and efficiency. Our verification testing includes multiple tests<br />

for force and suction to help create valves that don’t exhibit some of the common<br />

issues with reusable and other single-use valves: clogging, sticking and loss of<br />

insufflation. When you experience these issues during a procedure, the result<br />

can be a longer, more difficult procedure.<br />

In the range there is the DEFENDO Single Use Y-OPSY Valve, for when the<br />

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This product allows the user to biopsy and irrigate simultaneously through the<br />

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The newest addition to the DEFENDO range is the DEFENDO Single Use<br />

Cleaning Adapter for OLYMPUS ® endoscopes, used to flush the air/water<br />

channel after the procedure as a first step in the manual cleaning process.<br />

This can help prevent biofilm formation and is seen as one of the most<br />

important steps in cleaning and disinfecting an endoscope.<br />

Available in kits that include, Air/Water, Suction and Biopsy Valves, the DEFENDO<br />

range is compatible with Olympus, Pentax and Fujinon endoscopes. For more<br />

information and/or a free sample please contact your STERIS UK Endoscopy<br />

representative.<br />

Designed in the UK by TGDH<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

3


EDITOR’S COMMENT<br />

EDITOR’S COMMENT<br />

Looking beyond the typical.<br />

“Whilst medical<br />

conditions<br />

and diseases<br />

commonly<br />

present with<br />

classical<br />

symptoms<br />

there are also a<br />

host of atypical<br />

presentations<br />

that one must<br />

be aware and<br />

mindful of.”<br />

The differential diagnosis is one of the cornerstones of the medical profession and directs our patient<br />

assessment from the very beginning. From medical students to senior clinicians, it is an everyday part<br />

of clinical practice. Whilst medical conditions and diseases commonly present with classical symptoms,<br />

there are also a host of atypical presentations that one must be aware and mindful of. When the diagnosis<br />

is not forthcoming, we must look beyond the typical.<br />

In this edition of <strong>Gastroenterology</strong> <strong>Today</strong> we present two feature articles. The first highlighting the liver<br />

manifestations of coeliac disease and the importance of exploring the possibility of coeliac disease as<br />

a diagnosis in patients with elevated liver enzymes of unknown aetiology. In the second feature, the authors<br />

encourage clinicians to look beyond disease activity and anaemia in inflammatory bowel disease patients<br />

presenting with fatigue, with the recommendation that these patients should be screened for possible<br />

sub-clinical depression.<br />

Aaron Bhakta<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

4


TRIAGE GASTROSCOPY<br />

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GastroPanel® is a simple and effective noninvasive<br />

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recommend that individuals with extensive gastric<br />

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to closely monitor their disease. Early detection of<br />

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GastroPanel is a simple, effective and low cost blood<br />

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Advertorial feature<br />

What is the ideal treatment strategy for mild to moderate ulcerative<br />

colitis: early treatment escalation or mesalazine optimisation?<br />

Dr Anups de Silva<br />

Consultant Gastroenterologist<br />

and IBD Lead Clinician<br />

Norfolk and Norwich University<br />

Hospitals NHS Foundation Trust<br />

With the advent of novel biologics and small molecules, and the increasing<br />

availability of advanced diagnostic and management tools, the aspirations<br />

for patients with ulcerative colitis (UC) are higher than ever. As such,<br />

the International Organization for the Study of Inflammatory Bowel Disease<br />

have updated their short- and long-term treatment targets for patients with<br />

inflammatory bowel disease (IBD): 1<br />

• Systemic response<br />

• Symptomatic remission and normalisation of C-reactive protein<br />

• Decrease in calprotectin to an acceptable range; normal growth in children<br />

• Endoscopic healing; normalised quality of life and absence of disability<br />

However, the role and timing of treatment escalation to achieve these goals is a<br />

key area of debate. 2 Should we utilise these newer therapies as soon as patients<br />

are eligible for them, or should we ensure that first-line established therapies,<br />

such as mesalazine, have been fully optimised before treatment escalation?<br />

Treatment strategies should be tailored to patients’<br />

disease course<br />

Whilst treatment must be tailored to the severity of patients’ disease, it is likely<br />

to change over time. 2–4<br />

A 20-year, prospective, population-based study found that 69% of patients<br />

(n=340) had a disease course characterised by initially highly-active disease<br />

followed by long-term remission or instances of mild intestinal symptoms. 4<br />

Therefore, many patients may achieve good outcomes without the need for<br />

early intervention with biologics. 4<br />

The most common long-term disease course in patients with UC 4<br />

Initially highly-active disease<br />

followed by remission or mild 69%<br />

intestinal symptoms<br />

0 years 20 years<br />

Adapted from Monstad et al. 2021. 4<br />

Early anti-TNF use does not reduce hospitalisation and<br />

surgery rates<br />

In a retrospective study in patients with UC (n=318), early anti-tumour necrosis<br />

factor (TNF) use (≤2 years after diagnosis) had no effect on hospitalisation and<br />

surgery rates compared with anti-TNF use >2 years after diagnosis. 5<br />

Disease activity<br />

In addition to the lack of evidence supporting general early anti-TNF use in UC,<br />

several challenges must also be considered when determining the optimal<br />

treatment strategy:<br />

1<br />

2<br />

3<br />

A Cochrane review examining the adverse effects of biologics concluded<br />

that they were associated with statistically significantly higher rates of<br />

serious infection, tuberculosis reactivation, total adverse events (AEs) and<br />

withdrawal due to AEs compared with control treatment. 6 A separate<br />

Cochrane review into the use of mesalazine for the maintenance of<br />

remission of UC found little or no difference between mesalazine and<br />

placebo in commonly reported AEs. These included flatulence, abdominal<br />

pain, nausea, diarrhoea, headache and dyspepsia 7<br />

Early use may limit the effectiveness of treatment, as previous anti-TNF<br />

use is associated with a heightened probability of treatment failure and loss<br />

of response with subsequent anti-TNF therapy 8<br />

Anti-TNF therapies are vastly more expensive than standard first-line<br />

treatments such as mesalazine. 9 Even in the age of biosimilars, a single<br />

dose of an anti-TNF can cost more than a whole year’s treatment<br />

with mesalazine 9<br />

Mesalazine optimisation remains the recommended<br />

treatment strategy<br />

The British Society of <strong>Gastroenterology</strong> recommend optimising the use of<br />

first-line mesalazine treatment in patients with mild to moderate UC before<br />

escalating to other therapies by: 3<br />

• Increasing the dose up to 4–4.8g/day for the induction of remission<br />

• Combining oral and rectal mesalazine (sometimes referred to as ‘top and tail<br />

treatment’) for patients with an incomplete response<br />

• Tailoring the choice of formulation to take into account patients’ preferences,<br />

likely adherence and cost<br />

These strategies can have a profound effect on the outcomes that can be<br />

achieved with mesalazine. 10–13<br />

Dr de Silva’s case study: mesalazine dose optimisation to<br />

control a flare<br />

Patient characteristics:<br />

• 37-year-old male<br />

• 2-year history of left-sided UC<br />

• Treated with Octasa ® 2.4g/day taken once-daily<br />

Presenting complaint:<br />

• For 3 weeks he had been experiencing an increased frequency of<br />

looser-consistency bowel movements (4 times per day and once at night)<br />

with increased urgency, tenesmus and blood on most occasions<br />

• Admitted to periods of non-compliance due to a heavy work schedule and<br />

personal stresses<br />

Investigations:<br />

• Stool samples were sent for analysis with enteric pathogen polymerase chain<br />

reaction (PCR) and Clostridioides difficile assay. Both were negative<br />

• Faecal calprotectin was 1,424µg/g<br />

• A flexible sigmoidoscopy revealed a Mayo Clinic Score of 2 and colitis<br />

extending to the descending colon, with solid stool beyond this<br />

Solution:<br />

• His treatment was optimised by:<br />

– Increasing the dose of Octasa ® to 4.8g/day, taken in 2 divided doses<br />

– Starting treatment with a 1g mesalazine liquid enema at night, along with<br />

an Octasa ® 1g suppository 12 hours apart from the enema<br />

• During reassessment 10 days later, his bowel movement frequency had<br />

reverted back to his normal habit of twice daily with a more solid stool


Mesalazine optimisation can increase response rates vs<br />

standard dosing<br />

In a randomised, multicentre induction trial with an open-label extension,<br />

patients with moderately active UC and moderate/severe mucosal inflammation<br />

initially received Octasa ® 3.2g/day for 8 weeks (n=817). 10 At week 8, patients<br />

had their doses adjusted depending on their response to treatment, with those<br />

who did not respond having their dose increased to 4.8g/day. 10<br />

Response rate after increasing the dose of Octasa ® in patients with<br />

moderate UC who did not respond to initial treamtent 10<br />

Non-responders to<br />

Octasa ® 3.2g/day at<br />

week 8 (n=243)<br />

Adapted from D’Haens et al. 2017. 10<br />

Dose increase to<br />

4.8g/day for<br />

8 weeks (n=243)<br />

75.3% achieved a response<br />

with Octasa ® optimisation<br />

(n=183/243)<br />

Mesalazine optimisation can allow more patients to achieve<br />

mucosal healing vs standard dosing<br />

A post-hoc analysis of two prospective 6-week, double-blind, randomised studies<br />

compared mucosal healing rates (defined as a Mayo endoscopy subscore of 0 or 1)<br />

in patients with moderate UC who received 2.4g/day vs 4.8g/day oral mesalazine. 11<br />

Of those patients treated with 4.8g/day, 80% achieved mucosal healing vs only<br />

68% treated with 2.4g/day (n=322; p=0.012). Furthermore, mucosal healing<br />

was found to be well correlated with clinical response and improvement in<br />

patient-reported quality of life. 11<br />

Mesalazine optimisation can reduce treatment costs vs<br />

standard treatment<br />

Modelled data from meta-analyses were used to compare mesalazine dose<br />

optimisation (using the maximum dose, and combined oral and rectal therapy<br />

before treatment escalation) with standard treatment in 10,000 patients with<br />

mild to moderate UC. 12 It found mesalazine dose optimisation:<br />

• Increased the initial remission rate from 47% to 66%<br />

(n=4,725 vs n=6,565) 12<br />

• Potentially avoided AEs associated with other<br />

treatment classes, including psychological,<br />

gastrointestinal, dermatological and haematological<br />

AEs, infections and injection/infusion-related<br />

reactions 12<br />

Despite greater initial acquisition costs of increased mesalazine doses, the<br />

substantial improvements in patient outcomes associated with mesalazine dose<br />

optimisation resulted in net annual savings of £272 per patient. 12 With over<br />

200,000 people living with mild to moderate UC in the UK, it has the potential<br />

to save the NHS over £54 million per year. 12,14,15<br />

Mesalazine optimisation can help meet patient preferences<br />

Up to 3 in 5 patients have been found to be non-adherent to mesalazine in<br />

observational studies. 16–19 However, prescribing mesalazines according to<br />

patients’ preferences may help to improve this and reduce their risk of<br />

relapse. 13,19 Patients should be prescribed a mesalazine that gives them the<br />

number of tablets per administration, number of administrations per day and<br />

treatment appearance that they prefer. 13<br />

Mesalazine optimisation is the clear choice for mild to<br />

moderate UC<br />

Mesalazine optimisation should be employed before early treatment escalation<br />

due to the available evidence:<br />

• The majority of patients’ disease courses do not warrant early anti-TNF use 4,5<br />

• Early anti-TNF use can pose several challenges, including reduced<br />

effectiveness when anti-TNFs are used subsequently and high costs 8,9<br />

• Mesalazine optimisation can increase rates of response and mucosal<br />

healing, meet patients’ preferences and limit treatment costs vs standard<br />

dosing and treatment 10–13<br />

References: 1. Turner D et al. <strong>Gastroenterology</strong> 2021; 160(5): 1570–1583. 2. Raine T et al. J Crohns Colitis 2022; 16(1): 2–17. 3. Lamb CA<br />

et al. Gut 2019; 68(Suppl 3): s1–s106. 4. Monstad IL et al. J Crohns Colitis 2021; 15(6): 969–979. 5. Targownik LE et al. Clin Gastroenterol<br />

Hepatol 2022; 20(11): 2607–2618.e14. 6. Singh JA et al. Cochrane Database Syst Rev 2011; 2: CD008794. 7. Murray A et al. Cochrane<br />

Database Syst Rev 2020; 8: CD000544. 8. Atreya R et al. Front Med (Lausanne) 2020; 7: 517. 9. BNF. Accessed online, August <strong>2023</strong>.<br />

10. D’Haens GR et al. Aliment Pharmacol Ther 2017; 46(3): 292–302. 11. Lichtenstein GR et al. Aliment Pharmacol Ther 2011; 33(6):<br />

672–678. 12. Louis E et al. BMJ Open Gastroenterol 2022; 9(1): e000853. 13. MacKenzie-Smith L et al. Inflamm Intest Dis 2018; 3(1):<br />

43–51. 14. Crohn’s and Colitis UK. Epidemiology Summary: Incidence and Prevalence of IBD in the United Kingdom. Available at: https://<br />

crohnsandcolitis.org.uk/media/4e5ccomz/epidemiology-summary-final.pdf [accessed August <strong>2023</strong>]. 15. Schreiber S et al. J Crohns Colitis<br />

2013; 7(6): 497–509. 16. Testa A et al. Patient Prefer Adherence 2017; 11: 297–303. 17. Kane SV et al. Am J Gastroenterol 2001; 96(10):<br />

2929–2933. 18. Shale MJ et al. Aliment Pharmacol Ther 2003; 18(2): 191–198. 19. Kane SV et al. Am J Med 2003; 114(1): 39–43.<br />

OCTASA 1g Suppositories (mesalazine) - Prescribing Information<br />

Presentation: Suppository containing 1g mesalazine. Indications: Treatment of acute mild to moderate ulcerative proctitis. Maintenance of<br />

remission of ulcerative proctitis Dosage and administration: Adults and older people: Acute treatment - one Octasa 1 g Suppository once<br />

daily (equivalent to 1 g mesalazine daily) inserted into the rectum. Maintenance treatment - one Octasa 1 g Suppository once daily (equivalent<br />

to 1 g mesalazine daily) inserted into the rectum. Children: Limited experience and data for use in children. Method of administration: for<br />

rectal use, preferably at bedtime. Duration of use to be determined by the physician. Contra-indications: Hypersensitivity to salicylates<br />

or any of the excipients, severe impairment of hepatic or renal function. Warnings and Precautions: Blood tests and urinary status (dip<br />

sticks) should be determined prior to and during treatment, at discretion of treating physician. Caution in patients with impaired hepatic<br />

function. Do not use in patients with impaired renal function. Consider renal toxicity if renal function deteriorates during treatment. Cases<br />

of nephrolithiasis have been reported with mesalazine treatment. Ensure adequate fluid intake during treatment. Monitor patients with<br />

pulmonary disease, in particular asthma, very carefully. Patients with a history of adverse drug reactions to sulphasalazine should be kept<br />

under close medical surveillance on commencement of therapy, discontinue immediately if acute intolerance reactions occur (e.g. abdominal<br />

cramps, acute abdominal pain, fever, severe headache and rash). Severe cutaneous adverse reactions (SCARS), including Drug reaction with<br />

eosinophilia and systemic symptoms (DRESS), Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported.<br />

Stop treatment immediately if signs and symptoms of severe skin reactions are seen. Mesalazine may produce red-brown urine discoloration<br />

after contact with sodium hypochlorite bleach (e.g. in toilets cleaned with sodium hypochlorite contained in certain bleaches). Interactions:<br />

No interaction studies have been performed. May increase the myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine.<br />

May decrease the anticoagulant activity of warfarin. Fertility, pregnancy and lactation: Only to be used during pregnancy and lactation<br />

when the potential benefit outweighs the possible risk. No effects on fertility have been observed. Adverse reactions: Rare: Headache,<br />

dizziness, myocarditis, pericarditis, abdominal pain, diarrhoea, flatulence, nausea, vomiting, constipation, photosensitivity, Very rare: Altered<br />

blood counts (aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia), peripheral neuropathy, allergic<br />

and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis),<br />

acute pancreatitis, impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency, alopecia, myalgia,<br />

arthraligia, hypersensitivity reactions (such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis), changes in liver<br />

function parameters (increase in transaminases and parameters of cholestasis), hepatitis, cholestatic hepatitis, oligospermia (reversible). Not<br />

known: Nephrolithiasis, Drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis.<br />

Consult the Summary of Product Characteristics in relation to other adverse reactions. Marketing Authorisation Numbers, Package<br />

Quantities and basic NHS price: PL36633/0011; packs of 10 suppositories (£9.87) and 30 suppositories (£29.62). Legal category:<br />

POM. Marketing Authorisation Holder: Tillotts Pharma UK Ltd, The Larbourne Suite, The Stables, Wellingore Hall, Wellingore, Lincolnshire,<br />

LN5 0HX, UK. Octasa is a trademark. © 2021 Tillotts Pharma UK Ltd. Further Information is available from the Marketing Authorisation Holder.<br />

Date of preparation of PI: November 2022<br />

Adverse events should be reported. Reporting forms and information can be found at https://yellowcard.mhra.gov.uk.<br />

Adverse events should also be reported to Tillotts Pharma UK Ltd. (address as above) Tel: 01522 813500.<br />

OCTASA 400mg, 800mg & 1600mg Modified Release Tablets (mesalazine) - Prescribing Information<br />

Presentation: Modified Release tablets containing 400mg, 800mg or 1600mg mesalazine. Indications: All strengths: Ulcerative Colitis -<br />

Treatment of mild to moderate acute exacerbations. Maintenance of remission. 400mg & 800mg only: Crohn’s ileocolitis - Maintenance of<br />

remission. Dosage and administration: 400mg & 800mg tablets – Adults: Mild acute disease: 2.4g once daily or in divided doses, with<br />

concomitant steroid therapy where indicated. Moderate acute disease: 2.4g – 4.8g daily. 2.4g may be taken once daily or in divided doses,<br />

higher doses should be taken in divided doses. Maintenance therapy: 1.2g – 2.4g once daily or in divided doses. 1600mg tablets – Adults:<br />

Acute exacerbations: up to 4.8g, once daily or in divided doses. Maintenance: 1600mg daily. Tablets must be swallowed whole. Elderly:<br />

400mg & 800mg - normal adult dose may be used unless liver or renal function is severely impaired. 1600mg - no studies in elderly patients<br />

have been conducted. Children: 400mg & 800mg - limited documentation of efficacy in children >6 years old. Dose to be determined<br />

individually. Generally recommended that half the adult dose may be given to children up to a body weight of 40 kg; and the normal adult<br />

dose to those above 40 kg. 1600mg – safety and efficacy not established in children. Contra-indications: Hypersensitivity to salicylates,<br />

mesalazine or any of the excipients, severe impairment of hepatic or renal function (GFR less than 30 ml/min/1.73m 2 ). Warnings and<br />

Precautions: Urinary status (dip sticks) should be determined prior to and during treatment, at discretion of treating physician. Caution<br />

in patients with raised serum creatinine or proteinuria. Stop treatment immediately if renal impairment is evident. Cases of nephrolithiasis<br />

have been reported with mesalazine treatment. Ensure adequate fluid intake during treatment. Severe cutaneous adverse reactions<br />

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necrolysis (TENS) have been reported. Stop treatment immediately if signs and symptoms of severe skin reactions are seen. Haematological<br />

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reactions occur (e.g. abdominal cramps, acute abdominal pain, fever, severe headache and rash). Use with caution in patients with gastric<br />

or duodenal ulcers. Intact 400mg & 800mg tablets in the stool may be largely empty shells. If this occurs repeatedly patients should consult<br />

their physician. Use with caution in the elderly, subject to patients having normal or non-severely impaired renal and liver function. Patients<br />

with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take<br />

the 400mg or 800mg tablets. Mesalazine may produce red-brown urine discoloration after contact with sodium hypochlorite bleach (e.g.<br />

in toilets cleaned with sodium hypochlorite contained in certain bleaches). Interactions: No interaction studies have been performed.<br />

May decrease the anticoagulant activity of warfarin. Caution when used with known nephrotoxic agents such as NSAIDs, methotrexate<br />

and azathioprine. May increase the myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine. Monitoring of blood cell<br />

counts is recommended if these are used concomitantly. Fertility, pregnancy and lactation: Only to be used during pregnancy and<br />

lactation when the potential benefit outweighs the possible risk. No effects on fertility have been observed. Adverse reactions: Common:<br />

dyspepsia, rash. Uncommon: eosinophilia (as part of an allergic reaction), paraesthesia, urticaria, pruritus, pyrexia, chest pain. Rare:<br />

headache, dizziness, myocarditis, pericarditis, abdominal pain, diarrhoea, flatulence, nausea, vomiting, photosensitivity. Very rare: altered<br />

blood counts (aplastic anemia, agranulocytosis, pancytopenia, neutropenia, leucopenia, thrombocytopenia), blood dyscrasia, hypersensitivity<br />

reactions (such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis), peripheral neuropathy, allergic and fibrotic lung<br />

reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), interstitial pneumonia,<br />

eosinophilic pneumonia, lung disorder, acute pancreatitis, changes in liver function parameters (increase in transaminases and cholestasis<br />

parameters), hepatitis, cholestatic hepatitis, alopecia, myalgia, arthralgia, impairment of renal function including acute and chronic interstitial<br />

nephritis and renal insufficiency, renal failure which may be reversible on withdrawal, nephrotic syndrome, oligospermia (reversible). Not<br />

known: Drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson Syndrome, toxic epidermal necrolysis, pleurisy, lupuslike<br />

syndrome with pericarditis and pleuropericarditis as prominent symptoms as well as rash and arthralgia, nephrolithiasis, intolerance<br />

to mesalazine with C-reactive protein increased and/or exacerbation of symptoms of underlying disease, blood creatinine increased,<br />

weight decreased, creatinine clearance decreased, amylase increased, red blood cell sedimentation rate increased, lipase increased, BUN<br />

increased. Consult the Summary of Product Characteristics in relation to other adverse reactions. Marketing Authorisation Numbers,<br />

Package Quantities and basic NHS price: 400mg - PL36633/0002; packs of 90 tablets (£19.50) and 120 tablets (£26.00). 800mg -<br />

PL36633/0001; packs of 90 tablets (£40.38) and 180 tablets (£80.75). 1600mg – PL36633/0009; packs of 30 tablets (£30.08). Legal<br />

category: POM. Marketing Authorisation Holder: Tillotts Pharma UK Ltd, The Larbourne Suite, The Stables, Wellingore Hall, Wellingore,<br />

Lincolnshire, LN5 0HX, UK. Octasa is a trademark. © 2022 Tillotts Pharma UK Ltd. Further Information is available from the Marketing<br />

Authorisation Holder. Date of preparation of PI: November 2022<br />

Adverse events should be reported. Reporting forms and information can be found at https://yellowcard.mhra.gov.uk.<br />

Adverse events should also be reported to Tillotts Pharma UK Ltd. (address as above) Tel: 01522 813500.<br />

This advertorial has been funded and initiated by Tillotts Pharma UK (TPUK). The content in this<br />

advertorial has been driven by Dr de Silva and written by TPUK. Dr de Silva has reviewed the<br />

content, and TPUK have ensured technical accuracy and compliance with appropriate regulations<br />

and legislation.<br />

Date of preparation: August <strong>2023</strong>. PU-01292.


FEATURE<br />

CELIAC DISEASE RELATED LIVER<br />

MANIFESTATIONS IN TWO CASE<br />

STUDY PATIENTS<br />

RESEARCH<br />

Key words: celiac, gluten free, dietitian, liver, elevated liver enzymes<br />

Kathleen Eustace, MPH, RDN, LD, CNSC Corresponding Author<br />

UT Southwestern Medical Center Department of Clinical Nutrition<br />

Associate professor<br />

6011 Harry Hines Blvd. Dallas, TX 75390-8877<br />

214-648-1520<br />

kathleen.eustace@utsouthwestern.edu<br />

Alicia Gilmore, MS, RD, CSO, LD<br />

UT Southwestern Medical Center Department of Clinical Nutrition<br />

Associate professor<br />

6011 Harry Hines Blvd. Dallas, TX 75390-8877<br />

214-648-1520<br />

alicia.gilmore@utsouthwestern.edu<br />

Funding/ Support Disclosure: No funding was received for this article.<br />

Conflict of Interest: Neither author has any conflict of interests to report.<br />

Abstract<br />

from exposure of dietary gluten. CD primarily affects the small intestine<br />

and resolves with a gluten free diet (1). Classic presentation includes<br />

diarrhea, gassiness, abdominal pain, iron deficiency anemia, and weight<br />

loss. Organs, connective tissues, skin, joints, and the nervous system<br />

can also be affected by the systemic inflammatory response to gluten<br />

(2). Non-gastrointestinal manifestations include joint pain, dermatitis<br />

herpetiformis, low bone mineral density, and liver disease which<br />

manifests initially as elevated alanine and aspartate aminotransferase<br />

(ALT and AST, respectively) (1, 3). Diagnostic evaluation of CD should be<br />

completed with any range of symptoms without an alternative etiology,<br />

not just with presentation of historically associated symptoms.<br />

Elevated transaminase levels, or liver function tests (LFTs), can be<br />

a primary, and often overlooked, symptom of CD in the absence of<br />

additional symptoms (3, 4, 5, 6, 7, 8). Elevated LFT levels are reported<br />

in 40% of adults and 60% of children with CD (8). Undiagnosed celiac<br />

disease accounts for 9% of patients with transaminase elevations of<br />

unknown etiology (9, 10). The cause of CD related liver involvement<br />

is unclear, but literature suggests a possible mechanism is increased<br />

intestinal permeability of CD, allowing toxins and inflammatory mediators<br />

to reach the liver via the lymphatic system (11). Dietary therapy will<br />

reverse CD related liver disease, potentially preventing progression to<br />

overt liver failure (3, 11).<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

Celiac sprue or Celiac disease (CD) is an autoimmune disease that<br />

resolves with the removal of gluten from the diet. Traditionally CD<br />

presents with weight loss, iron deficiency anemia, and gastrointestinal<br />

symptoms such as gas, pain, and/or bloating. However, there is an<br />

increasing prevalence of novel presentations of CD, such as dermatitis<br />

herpetiformis, joint pain, and elevated transaminase levels. Elevated<br />

transaminase levels are cited in literature as the only presentation of<br />

celiac disease. Progression to liver disease and even liver failure can<br />

occur if not addressed in early stages with the initiation of a gluten<br />

free diet. Physician awareness of CD related liver involvement is of the<br />

upmost importance for both diagnosis and dietary nonadherence.<br />

Registered Dietitian Nutritionists (RDN) specializing in gluten free diets<br />

are poised to provide in-depth diet initiation and adherence support.<br />

RDNs can also perform the important task of educating on long term<br />

adherence to prevent poor outcomes including liver disease. This case<br />

study reviews two patients presenting with CD related transaminase<br />

elevations without other clinical manifestations. The purpose of this<br />

review is to highlight the importance of recognizing CD as an etiology<br />

for elevated transaminase levels and the valuable role the RDN plays<br />

in supporting dietary treatment to prevent and treat CD related liver<br />

disease.<br />

Background<br />

Celiac sprue or Celiac disease (CD) is an autoimmune disorder resulting<br />

Strict adherence to the prescribed gluten free diet is paramount to the<br />

prevention of CD related liver disease. Nonadherence occurs in 25-<br />

40% of CD patients due to intentional and unintentional consumption<br />

of gluten resulting in persistence and/or recurrence of symptoms (12,<br />

13). Amelioration of symptoms that interfere with daily life supports<br />

compliance with the required diet. However, if symptoms are silent, they<br />

can be ignored by patients inclined to noncompliance with the gluten<br />

free diet. CD related LFT abnormalities without other conspicuous<br />

symptoms will often go unnoticed by the patient (3, 14, 15). Registered<br />

dietitian nutritionist (RDN) educating on prescribed dietary therapy<br />

will need to emphasize the risk of symptom occurrence with dietary<br />

noncompliance at initial and follow up visits. In this article, we report<br />

two cases of CD presenting solely with elevated LFTs. The first where<br />

the diagnosis was incidental to elevated levels, while the second<br />

demonstrates dietary non-compliance resulting in liver disease in the<br />

absence of other symptoms. All HIPAA (Health Information Patient<br />

Accountability Act) guidelines and privacy rules were followed with<br />

respect to using or accessing PHI in the review of the cases.<br />

Case Study 1<br />

A 30-year-old Caucasian woman was referred to the <strong>Gastroenterology</strong><br />

Clinic for elevated transaminase levels found incidentally during a<br />

pre-operative evaluation. Past medical history included thyroid cancer<br />

with full thyroidectomy, type I diabetes, asthma, and childhood anemia.<br />

8


FEATURE<br />

A liver ultrasound was normal including size, texture, and echogenicity.<br />

Immunoglobulin G and Immunoglobulin A antibodies were assessed<br />

with both levels within the normal range. The patient denied weight<br />

loss or gastrointestinal symptoms including diarrhea, gas, or post<br />

prandial abdominal pain. Etiologies of nonalcoholic fatty liver disease<br />

and hepatic glycogenosis (due to the patient’s diagnosis of type 1<br />

Diabetes Mellitus) were suspected. The patient was referred for an<br />

esophagogastroduodenoscopy (EGD) with biopsy. EGD was notable<br />

for erythematous mucosa in the antrum as well as flattened mucosa<br />

in the duodenum. Biopsies confirmed the diagnosis along with an<br />

elevated serum tissue transglutaminase. The patient received the CD<br />

diagnosis and a referral to an RDN. The completed nutrition assessment<br />

included both anthropometrics and 24-hour diet recall. There had been<br />

no change in weight prior to the visit or with the diagnosis of CD. Blood<br />

glucose concentrations were stable, with the patient using a Medtronic<br />

pump and Dexcom monitor. Transaminase levels are noted in Table 1.<br />

The patient admitted difficulty identifying hidden sources of gluten, as<br />

well as concerns for both eating out safely and the potential for nutrient<br />

deficiencies (iron, b vitamins). Formal gluten free diet education was<br />

provided and individualized to the patients’ need. Supplementation of<br />

a gluten free multivitamin and mineral supplement was recommended.<br />

Lifelong dietary adherence was emphasized with the patient as a<br />

requirement for long term positive outcomes. Dietary compliance with a<br />

gluten free diet was measured by normalization of LFTs and a reduction<br />

in tissue transglutaminase level at 5 months and 11 months respectively<br />

after initial diagnosis.<br />

Subsequent scheduled follow ups were cancelled by the patient,<br />

and she was lost to follow up.<br />

Case Study 2<br />

A 49-year-old Caucasian female with a history of CD presented for<br />

dietary re-education due to long-term gluten free diet non-adherence.<br />

The patient presented nine years prior with abdominal pain and irregular<br />

stool output including diarrhea and constipation. Serologies from an<br />

outside facility were consistent with a diagnosis of CD and an EGD with<br />

small bowel biopsy supported the diagnosis of CD. The patient received<br />

formal education on a gluten free diet at initial diagnosis. The patient<br />

reported good dietary adherence initially but gradually reintroduced<br />

gluten without recurrence of symptoms. Mildly elevated transaminase<br />

levels were noted four years after diagnosis but normalized until eight<br />

years after diagnoses (Table 2). No alternative etiology for her elevated<br />

LFTs was determined leading to the conclusion that her underlying<br />

CD and subsequent dietary noncompliance was the cause of her<br />

transaminase elevations. Subsequent serology revealed an elevated<br />

serum tissue transglutaminase. The patient reinitiated a gluten free diet<br />

and a formal RDN referral was placed. A nutrition assessment revealed<br />

normal weight status, supplementation of iron, calcium, and vitamin<br />

D, as well as recent initiation of gluten free diet. A diet recall revealed<br />

gluten ingestion via flour-based cake, bread, and foods with a high risk<br />

of cross contamination including specialty coffees, hot cereals, and<br />

foods cooked with unknown seasonings. Individualized formal education<br />

was provided to reinforce adherence to a gluten free diet. The RDN<br />

emphasized strict diet adherence to prevent further complications.<br />

Liver transaminase levels returned to normal limits six weeks after<br />

reinitiating a strict gluten free diet (Table 2). Follow up with the RDN<br />

was scheduled on an as needed basis.<br />

Discussion<br />

Fifteen to fifty-five percent of CD patients experience elevated<br />

transaminase levels and/or changes in liver morphology (1, 2, 3, 4, 5, 6,<br />

7, 8, 9, 10). Non-adherence to a gluten free diet can lead to progressive<br />

liver disease and advancement to cirrhosis and liver failure in some<br />

individuals (3). Adherence to a gluten free diet is critical to prevent CD<br />

related liver disease progression. Both physicians and RDNs should<br />

recognize nonstandard presentations of CD. Case 1 highlights the<br />

importance of recognizing and diagnosing CD in the setting of isolated<br />

transaminase elevations. An inclusive work up with a liver panel and tissue<br />

Table 1 Liver Chemistry Results Before and After Diagnosis of Celiac Disease<br />

Baseline 2 months 5 months 9 months 11 months<br />

Alk Phos (U/mL) 109 116 117 92<br />

Alpha 1 Antitrypsin 200<br />

ALT (U/mL) 59 56 29 23<br />

AST (U/mL) 38 37 20 22<br />

Tissue transglutaminase AB, IGA, S (U/mL) ≥100.0 7<br />

Table 2 Liver Chemistry Results After Diagnosis of Celiac Disease for Case 2<br />

Post 4 years Post 7 years Post 8 years a<br />

January April July October December<br />

AST (U/L) 60 29 61 53 45 38 22<br />

ALT (U/L) 68 24 41 37 52 52 29<br />

TTG (U/mL) 15.9<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

a<br />

Labs were drawn throughout the year due to the initial findings of hypertransaminemia<br />

9


FEATURE<br />

transglutaminase collected prior to diagnosis should be repeated after<br />

6-12 months of strict adherence to a gluten free diet (5). These tests act as<br />

an indicator of dietary adherence and disease activity. As with the patient<br />

in Case 1, transaminase levels are expected to return to normal on a strict<br />

gluten free diet.<br />

Case 2 highlights how CD patients non-compliant with dietary restrictions<br />

can expect morphological and/or systemic changes. Elevated liver<br />

transaminase levels were not part of her initial presentation, but an<br />

unexpected consequence of gluten reintroduction. Gradual introduction<br />

of gluten overtime without overt symptoms recurrence led to increased<br />

dietary noncompliance, as reported by the patient. Dietary education<br />

must emphasize adherence even after initial symptom resolution due to<br />

the underlying pathological changes that can occur with gluten ingestion<br />

in patients with CD. Physicians and RDNs should reinforce the importance<br />

of dietary adherence to prevent long term consequences of untreated<br />

CD. Emphasis should be placed on the risk associated with dietary nonadherence<br />

even in the absence of obvious clinical symptoms such as<br />

elevated plasma transaminase levels.<br />

Restrictive diets such as the gluten free diet can present a challenge.<br />

Education and reinforcement of a strict gluten free diet by an RDN can<br />

prevent poor dietary adherence (16). The Nutrition Care Manual ® , a<br />

nutrition intervention guide provided by the Academy of Nutrition and<br />

Dietetics. recommends ‘if the potential exists for a nutrition diagnosis<br />

to develop (i.e., dietary nonadherence), the registered dietitian should<br />

establish an appropriate method and interval for follow up (17). This<br />

guideline is designed to reinforce dietary adherence to prevent CD<br />

manifestations of severe negative consequence including not only the<br />

reviewed CD-related hepatic pathology reviewed here, but others such as<br />

an increased risk of certain cancers (1, 7). Unfortunately, neither patient<br />

was seen for follow up after initial diagnosis and consultation. Case 2 had<br />

no follow up with an RDN over the 8 years from initial CD diagnosis until<br />

liver complications developed. Likewise, case 1 failed to schedule a follow<br />

up consultation. Physician appointments with CD patients should include<br />

screening for dietary adherence with subsequent referral to RDNs as<br />

needed to reinforce adherence to a strict gluten free diet.<br />

gluten-free diet may reverse hepatic failure. <strong>Gastroenterology</strong>.<br />

2002;122(4):881-8.<br />

4. Korpimaki S, Kaukinen K, Collin P, Haapala AM, Holm P, Laurila K,<br />

et al. Gluten-Sensitive Hypertransaminasemia in Celiac Disease:<br />

An Infrequent and Often Subclinical Finding. American Journal of<br />

<strong>Gastroenterology</strong>. 2011;106(9):1689-96.<br />

5. Kamath PS. Clinical approach to the patient with abnormal liver<br />

test results. Mayo Clin Proc. 1996;71(11):1089-94; quiz 94-5.<br />

6. Rubio-Tapia A, Murray JA. The liver in celiac disease. Hepatology.<br />

2007;46(5):1650-8.<br />

7. Sainsbury A, Sanders DS, Ford AC. Meta-analysis: Coeliac<br />

disease and hypertransaminasaemia. Aliment Pharmacol Ther.<br />

2011;34(1):33-40.<br />

8. Rubio-Tapia A, Abdulkarim AS, Wiesner RH, Moore SB,<br />

Krause PK, Murray JA. Celiac disease autoantibodies in severe<br />

autoimmune liver disease and the effect of liver transplantation.<br />

Liver Int. 2008;28(4):467-76.<br />

9. Volta U, De Franceschi L, Lari F, Molinaro N, Zoli M, Bianchi FB.<br />

Coeliac disease hidden by cryptogenic hypertransaminasaemia.<br />

Lancet. 1998;352(9121):26-9.<br />

10. Bardella MT, Vecchi M, Conte D, Del Ninno E, Fraquelli M,<br />

Pacchetti S, et al. Chronic unexplained hypertransaminasemia may<br />

be caused by occult celiac disease. Hepatology. 1999;29(3):654-<br />

7.<br />

11. Villavicencio Kim J, Wu GY. Celiac Disease and Elevated Liver<br />

Enzymes: A Review. J Clin Transl Hepatol. 2021;9(1):116-24.<br />

12. Gladys K, Dardzinska J, Guzek M, Adrych K, Malgorzewicz<br />

S. Celiac Dietary Adherence Test and Standardized Dietician<br />

Evaluation in Assessment of Adherence to a Gluten-Free Diet in<br />

Patients with Celiac Disease. Nutrients. 2020;12(8).<br />

13. Hall NJ, Rubin GP, Charnock A. Intentional and inadvertent nonadherence<br />

in adult coeliac disease. A cross-sectional survey.<br />

Appetite. 2013;68:56-62.<br />

14. Hagander B, Berg NO, Brandt L, Norden A, Sjolund K,<br />

Stenstam M. Hepatic injury in adult coeliac disease. Lancet.<br />

1977;2(8032):270-2.<br />

15. Ludvigsson JF, Elfstrom P, Broome U, Ekbom A, Montgomery<br />

SM. Celiac disease and risk of liver disease: a general populationbased<br />

study. Clin Gastroenterol Hepatol. 2007;5(1):63- 9 e1.<br />

16. Nealis C LC, Hollenbeck C. The Recovery Experience of Celiac<br />

Patients Following a Gluten-Free Diet: An ExploratoryStudy.<br />

Journal of the Academy of Nutrition and Dietetics. 2016;116;<br />

9:A96.<br />

17. Dietetics AoNa. Celiac Disease. Nutrition Therapy Efficacy 2021<br />

[Available from: https://www.nutritioncaremanual.org/topic.<br />

cfm?ncm_category_id=1&lv1=5522&lv2=22684&lv3=269416&n<br />

cm_toc_id=269416&ncm_heading=Nutrition%20Care.<br />

Conclusion<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

Currently, a consensus regarding evaluation of CD in patients with nonclassical<br />

symptom presentations does not exist; however, exploration<br />

of CD as a diagnosis is recommended in those presenting with elevated<br />

transaminase levels of unknown etiology (1). Once diagnosed, education<br />

on the risk dietary nonadherence should be routinely emphasized by both<br />

the treating physicians and RDNs. Elevated transaminase and progressive<br />

liver disease is a specific long-term consequence of CD that can easily<br />

be overlooked as both a symptom of the disease and a sign of nonadherence<br />

to a gluten free diet.<br />

References<br />

1. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG<br />

clinical guidelines: diagnosis and management of celiac disease.<br />

Am J Gastroenterol. 2013;108(5):656-76.<br />

2. Tovoli F, De Giorgio R, Caio G, Grasso V, Frisoni C, Serra M, et al.<br />

Autoimmune Hepatitis and Celiac Disease: Case Report Showing<br />

an Entero-Hepatic Link. Case Rep Gastroenterol. 2010;4(3):469-<br />

75.<br />

3. Kaukinen K, Halme L, Collin P, Farkkila M, Maki M, Vehmanen<br />

P, et al. Celiac disease in patients with severe liver disease:<br />

10


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Dosage: maintenance Adults: of remission Once daily of 1 mild/moderate sachet of 3g granules, ulcerative 1 colitis. or 2 sachets Salofalk of<br />

1.5g 250mg granules tablets or (Ireland): 3 sachets as of an 1000mg anti-inflammatory 500mg granules in the management (equivalent of to<br />

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granules maintenance three of remission times daily) of mild if more to moderate convenient. ulcerative Maintenance: colitis. Dosage: 0.5g<br />

mesalazine Salofalk 250mg three tablets times - Adults daily and elderly: (morning, acute treatment midday 6 -12 and tablets evening) daily<br />

corresponding 3 divided doses. to Maintenance a total dose treatment of 1.5g mesalazine 6 tablets daily per in day. 3 divided For patients doses.<br />

known Salofalk to 500mg be at tablets increased (UK only): risk for 1 relapse or 2 tablets for 3 medical times daily. reasons Maintenance: or due to<br />

difficulties 1 tablet 3 times to adhere daily. Salofalk to three 1g tablets daily doses, (UK only): give 1 tablet 3.0g mesalazine three times daily. as a<br />

Salofalk granules – adults: acute treatment – once daily 1 sachet of 3g<br />

single daily dose, preferably in the morning. Children: There is only<br />

granules, 1 or 2 sachets of Salofalk 1.5g granules, 3 sachets of 500mg<br />

granules limited documentation or 3 sachets of for 1000mg an effect granules in children (equivalent (age to 6-18 1.5 – years). 3.0g<br />

mesalazine Children 6 daily), years preferably of age and taken older: in the Active morning. disease: Alternatively, To be the determined dose can<br />

be individually, taken divided starting three with doses. 30-50mg/kg/day Maintenance treatment once daily – 1 preferably sachet of 500mg in the<br />

granules morning 3 or times in divided daily (1.5g doses. mesalazine Maximum daily). dose: Where 75mg/kg/day. needed, 3.0g per The day total in<br />

a dose single should morning not dose exceed may be taken. the maximum Method of administration: adult dose. Maintenance oral. Tablets<br />

treatment: - taken whole To without be determined chewing, with individually, liquid, one starting hour before with meals. 15-30mg/kg/day Granules<br />

in<br />

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Duration of treatment is usually 8 weeks. To be determined by physician.<br />

adult<br />

Children<br />

dose.<br />

(all formulations):<br />

It is generally<br />

there<br />

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dose individual to those basis starting above with 40kg. 30-50mg/kg/day Method of administration: either once daily Taken (granules) on the or<br />

tongue in divided and doses swallowed, (tablets and without granules). chewing, Maximum with 75mg/kg/day. plenty of liquid. Total Contraindications:<br />

should not exceed Hypersensitivity recommended to adult salicylates dose. Maintenance or any of the - on excipients. individual<br />

dose<br />

Severe basis starting impairment with 15-30mg/kg/day of renal or hepatic in divided function. doses. Warnings/Precautions:<br />

Total dose should not<br />

Blood<br />

exceed<br />

tests<br />

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prior<br />

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to those above<br />

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Contra-indications:<br />

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impaired to salicylates hepatic or any of function. the excipients. Should Severe not impairment be used of in renal patients or hepatic with<br />

impaired function. Warnings/Precautions: renal function. Mesalazine-induced Blood tests and urinary renal toxicity status (dip should sticks) be<br />

considered should be determined if renal function prior deteriorates to and during during treatment. treatment. Caution Cases is of<br />

recommended in patients with impaired hepatic function. Should not be<br />

used in patients with impaired renal function. Mesalazine-induced renal<br />

toxicity should be considered if renal function deteriorates during treatment<br />

- stop treatment immediately in such cases. Cases of nephrolithiasis<br />

reported; ensure good hydration. Serious blood dyscrasias have been<br />

reported very rarely with mesalazine. Hematological investigations should<br />

be performed if patients suffer from unexplained haemorrhages, bruises,<br />

purpura, anaemia, fever or pharyngolaryngeal pain. Salofalk should be<br />

nephrolithiasis<br />

discontinued in case<br />

reported;<br />

of suspected<br />

ensure<br />

or confirmed<br />

good hydration.<br />

blood dyscrasia.<br />

Patients<br />

Cardiac<br />

with<br />

hypersensitivity reactions (myocarditis, and pericarditis) induced by<br />

pulmonary<br />

mesalazine have<br />

disease,<br />

been rarely<br />

in<br />

reported.<br />

particular<br />

Salofalk<br />

asthma,<br />

should<br />

should<br />

then be<br />

be<br />

discontinued<br />

carefully<br />

monitored. immediately. Patients with with pulmonary a history disease, of adverse in particular drug asthma, reactions should to<br />

preparations be carefully monitored. containing Severe sulphasalazine cutaneous should adverse be reactions kept under (SCARs), close<br />

medical including surveillance. drug reaction with If acute eosinophilia intolerance and systemic reactions symptoms e.g., abdominal (DRESS),<br />

cramps, Stevens-Johnson acute abdominal syndrome pain, (SJS) and fever, toxic severe epidermal headache necrolysis and (TEN), rash, occur, have<br />

stop been reported. treatment Discontinue immediately. treatment Severe at the cutaneous first appearance adverse of signs reactions and<br />

(SCARs), symptoms of including severe skin Stevens-Johnson reactions, such as skin syndrome rash, mucosal (SJS) lesions, and or toxic any<br />

other sign of hypersensitivity. Patients with a history of adverse drug reactions<br />

epidermal necrolysis (TEN), have been reported. Discontinue<br />

to preparations containing sulphasalazine should be kept under close<br />

treatment medical surveillance. at the first If appearance acute intolerance of signs reactions and symptoms e.g., abdominal of severe cramps, skin<br />

reactions, acute abdominal such pain, as skin fever, rash, severe mucosal headache lesions, and rash or occur, any stop other treatment sign of<br />

hypersensitivity. immediately. Tablets Salofalk may granules be excreted contain undissolved aspartame, in patients a source with the of<br />

phenylalanine ileocecal valve removed. that may Salofalk be harmful granules: for patients contain with aspartame, phenylketonuria. a source of<br />

Salofalk phenylalanine. granules May contain be harmful sucrose: to patients 0.02mg, with phenylketonuria. 0.04mg, 0.06mg Granules and<br />

0.12mg also contain (500mg/1g/1.5g sucrose: 0.04mg, and 0.08mg, 3g granules 0.12mg, respectively). 0.24mg (500mg/1g/1.5g<br />

Interactions:<br />

Specific<br />

and 3g granules<br />

interaction<br />

respectively).<br />

studies have<br />

Salofalk<br />

not<br />

tablets:<br />

been performed.<br />

For patients on<br />

Lactulose<br />

a sodiumcontrolled<br />

diet: the 250mg and 500mg tablets contain 48mg and 49mg of<br />

or<br />

similar<br />

sodium,<br />

preparations<br />

equivalent to 2.4%<br />

that<br />

and<br />

lower<br />

2.5%<br />

stool<br />

of the recommended<br />

pH: possible<br />

maximum<br />

reduction<br />

daily<br />

of<br />

mesalazine intake for sodium. release Urine from may granules be discoloured due to red-brown decreased after pH contact caused with by<br />

bacterial sodium hypochlorite metabolism bleach of lactulose. used in toilets. With Interactions: concomitant Specific treatment interaction with<br />

azathioprine, studies have not 6-mercaptopurine been performed. or thioguanine With concomitant consider treatment a possible with<br />

increase azathioprine, in their 6-mercaptopurine myelosuppressive or thioguanine, effects. There consider is weak a possible evidence increase that<br />

mesalazine their myelosuppressive might decrease effects. the anticoagulant There is weak effect evidence of warfarin. that mesalazine Use in<br />

pregnancy might decrease and the lactation: anticoagulant There are effect no of adequate warfarin. data. Salofalk Do granules not use<br />

(additionally): lactulose, or similar preparations which lower stool pH:<br />

during pregnancy unless the potential benefit outweighs the possible<br />

possible reduction of mesalazine release from granules due to decreased pH<br />

risks. caused Limited by bacterial experience metabolism in the of lactulose. lactation Use period. in pregnancy Use during and lactation: breastfeeding<br />

do not use only Salofalk if the during potential pregnancy benefit unless outweighs the potential the possible benefit risks; outweighs if the<br />

infant the possible develops risks. Limited diarrhoea, experience breast-feeding the lactation should period. be Salofalk discontinued. should<br />

Undesirable only be used during effects: breast-feeding Headache, if dizziness, the potential peri- benefit and outweighs myocarditis, the<br />

abdominal possible risks; pain, if the diarrhoea, breast-fed dyspepsia, infant develops flatulence, diarrhoea, nausea, breast-feeding vomiting,<br />

aplastic should be discontinued. anaemia, agranulocytosis, Undesirable effects: pancytopenia, altered blood counts neutropenia, (aplastic<br />

leukopenia,<br />

anaemia, agranulocytosis,<br />

thrombocytopenia,<br />

pancytopenia,<br />

peripheral<br />

neutropenia,<br />

neuropathy, allergic<br />

leukopenia,<br />

and<br />

thrombocytopenia), hypersensitivity reactions such as allergic exanthema,<br />

fibrotic<br />

drug fever,<br />

lung<br />

lupus<br />

reactions<br />

erythematosus<br />

(including<br />

syndrome,<br />

dyspnoea,<br />

pancolitis,<br />

cough,<br />

headache,<br />

bronchospasm,<br />

dizziness,<br />

alveolitis, peripheral neuropathy, pulmonary peri- eosinophilia, and myo-carditis, lung infiltration, allergic and pneumonitis), fibrotic lung<br />

acute reactions pancreatitis, (including dyspnoea, impairment cough, of renal bronchospasm, function including alveolitis, pulmonary acute and<br />

chronic eosinophilia, interstitial lung infiltration, nephritis pneumonitis), and renal insufficiency, abdominal nephrolithiasis,<br />

pain, diarrhoea,<br />

dyspepsia, flatulence, nausea, vomiting, acute pancreatitis, cholestatic<br />

hepatitis, hepatitis, rash, pruritus, photosensitivity – especially with preexisting<br />

skin conditions, alopecia, severe cutaneous adverse reactions<br />

(SCARs) including drug reaction with eosinophilia and systemic symptoms<br />

(DRESS), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis<br />

(TEN), arthralgia, myalgia, impairment of renal function including acute and<br />

chronic interstitial nephritis and renal insufficiency, nephrolithiasis, asthenia,<br />

fatigue, oligospermia (reversible), changes in hepatic function parameters,<br />

photosensitivity<br />

changes in pancreatic<br />

especially<br />

enzymes,<br />

with<br />

eosinophil<br />

pre-existing<br />

count<br />

skin<br />

increased.<br />

conditions,<br />

Legal<br />

alopecia,<br />

category:<br />

POM. Cost (UK - basic NHS price; Ireland - PtW): Salofalk 250mg tablets<br />

Stevens-Johnson<br />

(100s) £16.19; €13.48.<br />

syndrome<br />

Salofalk<br />

(SJS),<br />

500mg<br />

toxic<br />

tablets<br />

epidermal<br />

(100s) £32.38.<br />

necrolysis<br />

Salofalk<br />

(TEN),<br />

1g<br />

myalgia, tablets (90s) arthralgia, £58.50. Salofalk hypersensitivity 500mg granules reactions (100 sachets) such £28.74; as allergic €27.93.<br />

exanthema, Salofalk 1000mg drug granules fever, lupus (50 sachets) erythematosus £28.74; €32.87. syndrome, Salofalk pancolitis, 1500mg<br />

changes granules in (60 hepatic sachets) function £48.85; parameters, €49.66. Salofalk hepatitis, 3g granules cholestatic (60 hepatitis sachets)<br />

and £97.70; oligospermia €101.64. (reversible), Product licence asthenia, number: fatigue, Salofalk changes 250mg in pancreatic tablets:<br />

enzymes, PL10341/0004; eosinophil PA573/4/3. count Salofalk increased. 500mg Legal tablets: category: PL08637/0019. POM. Salofalk Basic<br />

cost: 1g tablets: Salofalk PL08637/0027. 500mg granules, Salofalk pack size 500mg 100 sachets granules: - £28.74; PL08637/0007; €30.39.<br />

PA573/3/1. Salofalk 1000mg granules: PL08637/0008; PA573/3/2. Salofalk<br />

Salofalk 1000mg granules, pack size 50 sachets – £28.74; 32.87€.<br />

1500mg granules: PL08637/0016; PA573/3/7. Salofalk 3g granules:<br />

Salofalk PL08637/0025; 1.5g Granules, PA573/3/6. pack Product size 60 licence sachets holder: - £48.85; Salofalk €50.02. 250mg Salofalk tablets<br />

3g in Granules the UK: Dr pack Falk size Pharma 60 sachets UK Ltd, - Bourne £97.70; End €102.62 Business (UK- Park, NHS Cores price; End IE<br />

- Road, PtW). Bourne Product End, SL8 licence 5AS. Salofalk number: 500mg Salofalk and 1g tablets 500mg and granules all granules: –<br />

PL08637/0007; Dr Falk Pharma GmbH, PA573/3/1. Leinenweberstr.5, Salofalk 1000mg D-79108 granules Freiburg, – PL08637/0008;<br />

Germany. Date<br />

PA573/3/2. of preparation: Salofalk January 1.5g <strong>2023</strong> granules PL08637/0016; PA573/3/7. Salofalk<br />

3g granules PL08637/0025; PA573/3/6.Product licence holder: Dr Falk<br />

Pharma Further GmbH, information Leinenweberstr.5, is available on D-79108 request. Freiburg, Germany. Date of<br />

preparation: January 2022.<br />

Further Adverse information events should is available be reported. on request. In the UK: Reporting forms<br />

and information can be found at https://yellowcard.mhra.gov.<br />

Adverse uk/ In events Ireland: should Reporting be reported. forms Reporting and information forms and can information be found<br />

can at be https://www.hpra.ie/homepage/about-us/report-an-issue/<br />

found at https://yellowcard.mhra.gov.uk/ (UK residents) or in<br />

Ireland human-adverse-reaction-form<br />

at https://www.hpra.ie/homepage/about-us/report-anissue/human-adverse-reaction-form<br />

reported to Dr Falk Pharma UK Ltd Adverse at PV@drfalkpharma.co.uk.<br />

events should also be<br />

Adverse events should also be<br />

reported to Dr Falk Pharma UK Ltd at PV@drfalkpharma.co.uk<br />

References:<br />

References: 1. Salofalk Granules. Summary of Product Characteristics.<br />

1. 2. Salofalk Aldulaimi Granules. D et al. Summary Poster DRF16/057 of Product presented Characteristics. at the<br />

2. Aldulaimi BSG Annual D et Meeting, al. Poster June DRF16/057 2016, Liverpool presented UK. at the BSG Annual<br />

3. Meeting, Keil R et June al. Scand 2016, J Liverpool Gastroenterol UK. 2018; 21: 1-7.<br />

3. Keil R et al. Scand J Gastroenterol 2018; 21: 1-7.<br />

UC: ulcerative colitis<br />

UC: ulcerative colitis<br />

Date of preparation: March <strong>2023</strong><br />

Date<br />

UI--2300070<br />

of preparation: March 2022<br />

UI--2200080<br />

To find out more about Salofalk Granules<br />

watch this 60s animation


FEATURE<br />

FATIGUE IN PATIENTS WITH<br />

INFLAMMATORY BOWEL DISEASE—<br />

STRONGLY INFLUENCED BY DEPRESSION<br />

AND NOT IDENTIFIABLE THROUGH<br />

LABORATORY TESTING: A CROSS-<br />

SECTIONAL SURVEY STUDY<br />

Victoria Uhlir 1 , Andreas Stallmach 1 and Philip Christian Grunert 1 *<br />

Uhlir et al. BMC <strong>Gastroenterology</strong> (<strong>2023</strong>) 23:288 https://doi.org/10.1186/s12876-023-02906-0<br />

RESEARCH<br />

Background<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

Abstract<br />

Background: Fatigue is a debilitating and highly relevant symptom in<br />

patients with inflammatory bowel disease (IBD). However, awareness of<br />

fatigue and treatment options remains limited. This study was aimed at<br />

elucidating the influence of disease activity and common complications<br />

(pain, anemia, depression, anxiety and quality of life) on fatigue in patients<br />

with IBD to identify potential interventional targets for treating physicians.<br />

Methods: A cross-sectional survey including five questionnaires (HADS,<br />

Fatigue Assessment Scale, McGill Pain Questionnaire, IBDQ and general<br />

well-being) was performed on patients with IBD (n = 250) at a university<br />

IBD clinic. Additionally, demographic data, laboratory data, IBD history,<br />

treatment and current disease activity (Harvey-Bradshaw Index, partial<br />

Mayo Score, calprotectin and CRP) were recorded.<br />

Results: A total of 189 patients were analyzed (59.8% with Crohn’s<br />

disease (CD) and 40.2% with ulcerative colitis (UC)).<br />

A total of 51.3% were fatigued, and 12.2% were extremely fatigued.<br />

Multiple factors showed significant correlations in univariate analysis.<br />

Multivariate analysis revealed that fatigue was correlated with<br />

depression (CD, p = 0.002; UC, p = 0.02), diminished quality of life<br />

(CD, p = 0.015), female sex (CD, p = 0.015) and younger age (UC,<br />

p = 0.024), whereas the influence of anemia or disease activity was<br />

non-significant.<br />

Conclusions: Fatigue is burdensome and highly prevalent in<br />

patients with active and inactive IBD. Considerations for fatigue<br />

treatment, beyond targeting inflammation and anemia, should include<br />

investigation of underlying subclinical depression.<br />

Keywords: Fatigue, Crohn’s disease, Ulcerative colitis, Depression<br />

Inflammatory bowel diseases (IBDs) are relapsing inflammatory bowel<br />

conditions characterized by unclear etiology and an unpredictable<br />

disease course. In addition to inflammatory activity, psychosocial<br />

symptoms such as fatigue, persistent and extreme forms of mental<br />

and/or physical exhaustion, tiredness or weakness occur [1]. In some<br />

patients, the psychosocial symptoms of fatigue, is one of the most<br />

frequent symptoms in IBD. As many as 80% of patients with active<br />

disease and about 60% of patients in remission report this symptom<br />

and find it even more debilitating than urgency, diarrhea, flatulence<br />

and pain [3]. If left untreated, fatigue can increase over time [4]. Further<br />

studies from the USA and France have reported similar high incidence<br />

of fatigue (45–65%) in Crohn’s disease (CD) and ulcerative colitis<br />

(UC) [5, 6], at rates comparable to those observed with other chronic<br />

diseases such as cancer, multiple sclerosis or rheumatoid arthritis [7].<br />

Although fatigue is highly relevant [3, 8], it is not well understood by<br />

patients or practitioners [9], and it has received insufficient attention in<br />

previous years. One reason for the low recognition of fatigue in clinical<br />

consultations might be that fatigue assessment is challenging and<br />

not clearly defined. Particularly in time-limited outpatient visits, the<br />

psychosocial aspects of disease may be neglected, despite their high<br />

importance in patients with IBD [10].<br />

In previous studies, fatigue has been associated with depression [11–13],<br />

pain [14], anxiety [15, 16], low quality of life [12, 17], psychological wellbeing<br />

[4, 18], anemia [8, 19], and sex [20, 21]. The influence of disease<br />

activity is controversial. Some studies have reported that disease activity<br />

is a relevant factor [16, 22]. Physicians’ current management of fatigue<br />

consists primarily of addressing inflammatory activity and nutritional<br />

deficits. However, fatigue is highly prevalent even in quiescent disease<br />

[2, 7, 23], at levels above those in healthy controls [2], and an increase in<br />

*Correspondence:<br />

Philip Christian Grunert philip.grunert@med.uni-jena.de<br />

1<br />

Department of Internal Medicine IV, Jena University Hospital, Universitätsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany<br />

12


FEATURE<br />

fatigue over time is independent of disease pattern [4]. Thus, the causes<br />

can be assumed to be multifactorial, and the dependence of fatigue on<br />

potential influencing factors must be ruled out.<br />

and ≥ 35 points indicating extreme fatigue. In a comparison of six<br />

different fatigue questionnaires, the FAS has been found to be the<br />

most promising measure of fatigue with good reliability and validity [26].<br />

The aim of this study was to further elucidate the influence of disease<br />

activity and common complications, such as pain, anemia, depression,<br />

anxiety and decreased quality of life, on fatigue in patients with<br />

IBD, to identify potential interventional targets for daily practice. In<br />

a cross-sectional study, a sizeable IBD cohort was assessed with<br />

the Fatigue Assessment Scale (FAS), IBD disease activity clinical<br />

scores, paraclinical activity parameters and a large set of validated<br />

questionnaires.<br />

Patients and methods<br />

Study population<br />

This cross-sectional paper-based survey study was performed at the<br />

Department of Internal Medicine, Jena University Hospital, a third-level<br />

IBD clinic with approximately 2,100 patients with IBD. Patients were<br />

recruited by the hospital staff during outpatient visits.<br />

The inclusion criteria were 1) patients 18 years of age and older, 2)<br />

diagnosis of Crohn`s disease (CD) or ulcerative colitis (UC) and 3)<br />

German language proficiency.<br />

Data collection<br />

A total of 250 patients were asked to participate in the study between<br />

June 27, 2018 and November 11, 2018. After providing written<br />

consent, the patients completed five questionnaires evaluating<br />

fatigue, depression and anxiety, pain, health related quality of life and<br />

general well-being. Additionally, demographic information on sex, age,<br />

occupation and current medications was recorded. Disease activity<br />

was assessed by the treating physician. Laboratory values were<br />

obtained from blood results measured no more than 4 weeks before or<br />

after the appointment. Patients were included in the analysis when at<br />

least 95% of questionnaire items were completed.<br />

Measurements and instruments<br />

Ascertainment of anxiety and depression<br />

Anxiety and depression were assessed with the German version of<br />

the Hospital Anxiety and Depression Scale, a 14-item self-reported<br />

questionnaire with seven items each for the dimensions of depression<br />

(HADS-D) and anxiety (HADS-A). Each item is rated 0–3 according to<br />

severity, thus resulting in scores of 0–21 for each dimension [15]. A<br />

score of 8–10 indicates suspicion, and a score > 10 points indicates<br />

a disorder, of either anxiety or depression. This scale has been widely<br />

used in patients with IBD [11, 13, 15, 16].<br />

Ascertainment of quality of life<br />

The Inflammatory Bowel Disease Questionnaire (IBDQ) is a disease<br />

specific instrument used to assess the health-associated quality of life<br />

(QoL) in patients with IBD. We used the German version, which has been<br />

validated by Janke et al. It contains 32 items, each ranging from 1 (worst)<br />

to 7 (best), and assesses the QoL in four dimensions (bowel, systemic,<br />

emotional and social well-being) and provides a total score. Higher<br />

scores indicate better QoL [31]. For our correlations, we used only the<br />

total score.<br />

Ascertainment of pain<br />

The Short-Form McGill Pain Questionnaire is a well-established and<br />

widely used measure to evaluate pain [32, 33]. It consists of three<br />

parts. The first part assesses pain with adjectives, each graded<br />

from 0 (none) to 3 (severe), thus illustrating the sensory (11 Items)<br />

and affective (4 Items) component of pain (pain rating index). In<br />

the second part, pain is quantified on a 0–100 Visual analogue Scale<br />

(VAS). The present pain intensity is graded on a 5-point scale from<br />

0 (no pain) to 5 (excruciating) in the third part. The scores for the<br />

questionnaire can range from 0 to 45 on the pain rating index; from 0<br />

to 10 cm on the VAS; and from 0 to 5 on present pain intensity.<br />

Ascertainment of general well‐being<br />

Patients were asked to rate their current general well-being on a Global<br />

Assessment Scale ranging from 0 (very poor) to 100 (very good).<br />

Clinical evaluation of disease activity<br />

Disease activity in CD was assessed with the Harvey-Bradshaw Index<br />

(HBI) [24]. Scores < 5 points indicated remission, 5–7 points indicated<br />

mild disease, and higher scores indicated severe disease. UC disease<br />

activity was graded with the partial Mayo Score (pMayo) [25]. Scores<br />

< 2 points indicated remission, 2–4 points indicated mild disease, 5–6<br />

points indicated moderate disease, and 7–9 points indicated severe<br />

disease. Because the UC population was relatively small, we decided<br />

to include patients with moderate to severe disease in one group, to<br />

achieve better evaluation quality.<br />

Ascertainment of fatigue<br />

The FAS is a unidimensional ten item fatigue scale, which has<br />

previously been used for the general public [26, 27] and for more than<br />

26 other chronic diseases [27–30]. Each item is rated from 1 (never) to<br />

5 (always), thus resulting in a total score ranging from 10 to 50 points,<br />

with 10–21 points indicating no fatigue, 22–34 points indicating fatigue<br />

Clinical laboratory values<br />

To identify anemia, we evaluated hemoglobin (Hb), mean corpuscular<br />

volume and mean corpuscular hemoglobin. Systemic inflammation was<br />

assessed on the basis of the C-reactive protein (CRP), which we rated<br />

as normal for all values under 7 mg/l. For IBD specific inflammation, we<br />

used fecal calprotectin, a surrogate parameter for mucosal inflammation.<br />

Values under 100 mg/kg stool were rated as normal/remission, whereas<br />

values above 100 mg/kg indicated mucosal inflammation [34].<br />

Data analysis<br />

Descriptive analysis was performed with simple statistical standards,<br />

such as percentages and mean values. Bar charts, histograms, and<br />

box plots with percentages were used for presentation.<br />

All metric scaled scores and age were tested with the determined<br />

fatigue score with Pearson`s correlation coefficient and are presented<br />

in scatter plots. Values above 0.5 indicated a strong effect.<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

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FEATURE<br />

a N number of patients included for analysis<br />

Table 1 Socio-demographic characteristics<br />

CD N a UC N a Total N a<br />

Socio-demographic characteristics<br />

Total number of patients 113 (59.8%) 76 (40.2%) 189 189<br />

Age 38 (18 -74) 47 (19–80) 40 (18–80) 189<br />

Sex female/male 59/54 30/46 89/100 189<br />

Employed 73 (67.6%) 108 45 (62.5%) 72 118 (65.6%) 180<br />

Disease activity (HBI/partial Mayo) 104 71 175<br />

Remission 59 (56.7%) 32 (45.1%) 91 (52.0%)<br />

Mild disease 22 (21.2%) 23 (32.4%) 45 (25.7%)<br />

Moderate to severe disease 23 (22.1%) 16 (22.5%) 39 (22.3%)<br />

IBD Characteristics (Montreal) 112 76<br />

Age at Diagnosis<br />

A1 < 17 years 21 (18.8%)<br />

A2 17–40 years 68 (60.7%)<br />

A3 > 40 years 23 (20.5%)<br />

Location (CD = L, UC = E)<br />

L1 Terminal Ileum / E1 Proctitis 22 (19.6%) 2 (2.6%)<br />

L2 Colon / E2 Left-sided 28 (25%) 41 (53.9%)<br />

L3 Ileocolonic / E3 Pancolitis 47 (42%) 29 (38.2%)<br />

Upper and lower GI-tract (+L4) / Ileal pouch 15 (13.4%) 4 (5.3%)<br />

Behavior<br />

B1 non-stricturing/non-penetrating 39 (34.8%)<br />

B2 stricturing 30 (26.8%)<br />

B3 penetrating 16 (14.3%)<br />

B3p perianal disease 27 (24.1%)<br />

Table 2 Results of psychometric tests and laboratory values<br />

CD SD Min Max UC SD Min Max Total SD Min Max<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

Psychosocial factors (N a )<br />

FAS (189)<br />

No fatigue 41 (36.3%) 28 (36.8%) 69 (36.5%)<br />

Fatigue 60 (53.1%) 37 (48.7%) 97 (51.3%)<br />

Extreme fatigue 12 (10.6%) 11 (14.5%) 23 (12.2%)<br />

Mean value fatigue score 24.72 7.27 10 40 24.71 7.54 12 43 24.71 7.36 10 43<br />

IBDQ10) 20 (17.9%) 18 (24.0%) 38 (20.3%)<br />

HADS-D (depression) b (187) 5.04 4.1 0 17 5.41 3.78 0 16 5.19 3.96 0 17<br />

Indicating depression (>10) 15 (13.5%) 7 (9.2%) 22 (11.8%)<br />

McGill Pain Questionnaire (179)<br />

Total pain none/ low – mild 35 (32.7%) 26 (36.1%) 61 (34.1%)<br />

Total pain disstressing or worse 50 (46.7%) 32 (44.5%) 82 (45.8%)<br />

Sensoric component of pain b (181) 5.59 5.4 0 21 4.75 5.78 0 25 5.25 5.56 0 25<br />

Affective component of pain b (181) 2.63 3.08 0 12 2.12 2.56 0 11 2.43 2.89 0 12<br />

Current pain on VAS b (182) 1.94 2.26 0 8.3 1.16 1.73 0 7.2 1.6 2.06 0 8.3<br />

Laboratory values (N a )<br />

Anaemia (169) 33 (33.0%) 28 (40.6%) 61 (36.1%)<br />

CRP > 7 (163) 28 (28.9%) 16 (24.2%) 44 (27.0%)<br />

Fecal calprotectin > 100 mg/kg (60) 18 (46.2%) 17 (81.0%) 35 (58.3%)<br />

a N = number of patients included for analysis<br />

b Mean value<br />

14


FEATURE<br />

Fig. 1 Mean fatigue scores (FAS), separated by IBD type. Data is grouped boxplots. N = 189<br />

Table 3 Total fatigue score, tested against demographic factors/<br />

laboratory values with Mann–Whitney U-test<br />

p-value = p < 0.001<br />

N a =<br />

Employed b = employed, students and trainees<br />

Unemployed c = unemployed and retired<br />

Total fatigue score value<br />

Factors N a median (IQR)<br />

For mean value comparison, the variables to be tested were divided<br />

into groups, which were tested against each other on the basis of the<br />

achieved fatigue score. The groupings were as follows.<br />

p-value<br />

Anemia<br />

No 108 24 (19–30.75) 0.538<br />

Yes 61 24 (20–29.5)<br />

CRP<br />

Normal 119 24 (19–31) 0.109<br />

Elevated 44 22.5 (18–28)<br />

Fecal calprotectin<br />

Normal 25 25 (20–30.5) 0.898<br />

Elevated 35 24 (19–31)<br />

Sex<br />

Female 89 27 (23–31.5) < 0.001<br />

Male 100 21 (18–28)<br />

Diagnosis<br />

CD 113 24 (19.5–30) 0.838<br />

UC 76 24 (18–30.5)<br />

Employment status<br />

Employed B 134 24 (20–29) 0.357<br />

Unemployed C 46 25.5 (18–33)<br />

“elevated”; anemia: “yes” vs “no”; sex: “male” vs “female”; diagnosis:<br />

“CD” vs “UC”; disease activity: “remission” vs “moderate to severe<br />

disease”; anxiety and depression: “inconspicuous” vs “conspicuous,<br />

severe to very severe symptoms”; and overall assessment of intensity<br />

of pain: “non-low/mild” vs “distressing or worse.” Group analysis<br />

was performed with the Mann–Whitney U-test. values < 0.05 were<br />

considered significant. The Kruskal–Wallis test was used to assess<br />

fatigue differences within the disease location, behaviour and age at<br />

diagnosis groups.<br />

For nominal (anemia, CRP elevation or fecal calprotectin elevation) or<br />

ordinal (anxiety, depression, disease activity, quality of life or total pain)<br />

variables, rank chi squared test (with trend test from three variables)<br />

was performed, and cross tables were created. values < 0.05 were<br />

considered significant.<br />

To avoid a high number of missing cases in multiple linear regression<br />

analysis, we conducted a univariate analysis for each variable to screen<br />

for significant factors correlating with fatigue. For all metric scores<br />

(HBI, pMayo, HADS-A/D, IBDQ, current pain, total pain and GAS) and<br />

age, Pearson´s correlation coefficient was used. All nominal factors<br />

(anemia, CRP elevation, fecal calprotectin elevation, sex and diagnosis,<br />

surgery, medication, stoma) were tested by median comparison with<br />

Mann– Whitney U-test. All variables showing a significant correlation (<br />

< 0.05) in the univariate analysis, as well as sex and age, were included<br />

in multiple linear regression analysis. Multiple regression analysis was<br />

performed for CD and UC separately. All variables were tested for<br />

collinearity. Analyses were performed in IBM SPSS Statistics version<br />

25 (IBM Corp., Armonk, NY, USA).<br />

Ethical considerations<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

Laboratory values for CRP and fecal calprotectin: “normal” vs<br />

Ethical approval was granted by the Ethics Committee of the Jena<br />

15


FEATURE<br />

Fig. 2 Mean fatigue scores (FAS), separated by IBD type and sex. Data is displayed as grouped boxplots. N = 189<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

Table 4 Correlations among total scores of disease activity,<br />

psychosocial factors and age, and the FAS score<br />

p-value = p < 0.001<br />

a<br />

N =<br />

University Hospital, Jena, Germany (5530– 05/18), and all patients provided<br />

signed informed consent, according to the Declaration of Helsinki.<br />

Results<br />

A total of 250 patients were asked to participate in the study; 210<br />

patients consented to participate, among whom a total of 189 patients<br />

(76% response rate) completed at least 95% of the questionnaire<br />

items and thus were included in the analysis. A total of 113 (59.8%)<br />

patients had CD, and 76 (40.2%) patients had UC. Clinical and sociodemographic<br />

characteristics are presented in Table 1. The results of<br />

psychometric testing and laboratory values classified by type of IBD<br />

are shown in Table 2.<br />

Prevalence and severity of fatigue<br />

Total fatigue score value<br />

Total score value N a Pearson<br />

correlation p-value R2 - value<br />

HBI (for CD) 104 0.466 < 0.001 0.217<br />

Partial Mayo Score (for UC) 71 0.183 0.183 0.026<br />

HADS-A 187 0.616 < 0.001 0.379<br />

HADS-D 187 0.679 < 0.001 0.46<br />

IBDQ 186 -0.682 < 0.001 0.465<br />

Current pain (McGill-Pain-Q.) 182 0.358 < 0.001 0.128<br />

Total pain (McGill-Pain-Q.) 181 0.39 < 0.001 0.152<br />

GAS 178 -0.562 < 0.001 0.316<br />

Age 189 -0.012 0.869 1.449<br />

The mean FAS fatigue scores were 24.72 (median: 24, IQR: 19,5–30)<br />

and 24.71 (median 24, IQR: 18–30,5) for CD and UC, respectively (Fig.<br />

1), and no statistical difference between diagnoses was observed ( =<br />

0.838, Table 3). Two-thirds of patients were either fatigued (CD: 53.1%,<br />

UC: 48.7%) or extremely fatigued (CD: 10.7%, UC: 14.5%). Fatigue<br />

was significantly more frequent in women (80,9%) than in men (48,0%)<br />

(median fatigue score 27 vs 21, < 0.001, Table 3, Fig. 2). Because we<br />

did not find significant differences across IBD subtypes in univariate<br />

analyses for all factors, we decided not to distinguish by diagnosis,<br />

except for disease activity, for clarity of presentation in the tables.<br />

Fatigue and disease characteristics<br />

Fatigue was more often present in patients with moderate to severe<br />

disease activity than in patients in remission (CD: 95.7% vs 46.6%,<br />

UC: 75% vs 62.5%). This finding was significant in only CD ( < 0.001)<br />

but not UC ( = 0.80). In CD, 82.1% of the patients without fatigue<br />

were in remission, whereas 54.5% of those with extreme fatigue<br />

had moderate to severe disease. This weak positive correlation was<br />

statistically significant in univariate analysis ( < 0.001). Regarding<br />

disease characteristics beyond disease activity, no correlations were<br />

found between fatigue and age at diagnosis (H(2) = 0.183, = 0.913),<br />

disease location (H(3) = 1.09, = 0.779), or disease behaviour (H(3) =<br />

2.36, = 0.501) in patients with Crohn’s disease (CD) or disease location<br />

(H(3) = 0.507, = 0.917) in patients with ulcerative colitis (UC). In the HBI<br />

documented complications for CD (fistulas, erythema nodosum etc.)<br />

did not correlate with higher levels of fatigue. 22 patients reported<br />

having undergone bowel surgery. There was no significant influence<br />

of surgery on fatigue ( = 0.864). 5 patients had a stoma which also<br />

did not impact fatigue scores ( = 0.881). IBD specific medication did<br />

not influence fatigue levels (any IBD medication n = 162, p = 0.108;<br />

biologics n = 89, p = 0.351; mesalazine n = 64, p = 0.555; thiopurines<br />

n = 28, p = 0.439; steroids n = 48, p = 0.724).<br />

Psychosocial factors associated with fatigue<br />

Univariate factor analysis with Pearson´s correlation coefficient showed<br />

that anxiety, depression, health related quality of life, general well-being<br />

and pain were associated with the presence of fatigue and total fatigue<br />

score. The strongest correlations were found for quality of life and<br />

depression (Table 4, Figs. 3 and 4).<br />

Fatigue and anxiety<br />

Patients without conspicuous anxiety symptoms had significantly lower<br />

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FEATURE<br />

Fig. 3 Correlation of fatigue score (FAS) and depression score (HADS-D), separated by diagnosis.<br />

Data is displayed as grouped scatter plot. N = 187<br />

mean fatigue scores than patients with conspicuous anxiety symptoms<br />

(median fatigue scores: 21 vs 32, p < 0.001). A total of 83.8% of<br />

patients without fatigue showed unremarkable anxiety symptoms,<br />

whereas 60.9% of patients with extreme fatigue were classified as<br />

anxious with HADS-A (p < 0.001).<br />

Fatigue and depression<br />

Similar strong effects were found regarding depression. Whereas<br />

patients without depression had median fatigue scores of 22 points,<br />

the group classified as depressed according to HADS-D had a<br />

median fatigue score of 33 points (p < 0.001). Whereas 95.6% of<br />

the group without fatigue had no quantifiable depressive symptoms,<br />

the depression was severe to very severe in 43.5% of the extremely<br />

fatigued group.<br />

Fig. 4 Correlation of fatigue score (FAS) and depression score (HADS-D), separated by diagnosis.<br />

Data is displayed as grouped scatter plot. N = 187<br />

Fatigue and HRQoL<br />

Patients with fatigue or extreme fatigue significantly more often had<br />

low scores for the magnitude of active disease (IBDQ < 171) (extreme<br />

fatigue: 100%, fatigue: 71.9%, no fatigue: 25.4%, p < 0.001). A total of<br />

64.9% of the patients with IBDQ scores > 171 (suggestive of remission)<br />

had “no fatigue.” In contrast, 84.4% of the patients with low IBDQ<br />

scores experienced either fatigue or extreme fatigue. The majority of<br />

the 32 items and all of the 4 domains of the IBDQ showed a significant<br />

correlation with fatigue, as determined by Pearson’s correlation<br />

coefficient (Additional file 1). There were some exceptions, including<br />

UC items 1 (stool frequency), 5 (loose stools), 7 (worried about<br />

surgery), 17 (passing gas), 22 (rectal bleeding) as well as 26 (soiling),<br />

and CD item 22 (rectal bleeding). The strongest correlations for fatigue<br />

were observed for item 2 (tired / worn out) (UC: r(74) = -0.717, p = <<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

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FEATURE<br />

Table 5 Multiple linear regression analysis of factors associated with total fatigue score<br />

Crohn´s disease<br />

Ulcerative colitis<br />

Factors<br />

(95%CI)<br />

p-value*<br />

p-value*<br />

Female vs male 2.333 (0.466–4.199) 0.015 1.603 (-1.270–4.476) 0.268<br />

Age 0.067 (0.002–0.136) 0.057 -0.109 (-0.202—0.015) 0.024<br />

HBI/Partial Mayo Score -0.223 (-0.535–0.090) 0.160 -0.593 (-1.270–0.084) 0.085<br />

HADS-D 0.613 (0.231–0.996) 0.002 0.756 (0.126–1.386) 0.020<br />

HADS-A 0.177 (-0.187–0.541) 0.337 0.470 (-0.011–0.950) 0.055<br />

IBDQ -0.113 (-0.186–-0.041) 0.003 -0.032 (-0.110–0.046) 0.415<br />

GAS 0.010 (-0.063–0.082) 0.794 -0.019 (-0.105–0.067) 0.663<br />

Total pain (McGill-Pain-Q.) 0.058 (-0.104–0.221) 0.477 -0.051 (-0.246–0.145) 0.606<br />

Current pain (McGill-Pain-Q.) -0.168 (-0.949–0.613) 0.670 0.576 (-0.399–1.546) 0.239<br />

* = p < 0.05<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

0.001; CD: r(111) = -0.750, p = < 0.001), item 6 (energy) (UC: r(74) =<br />

-0.655, p = < 0.001); CD: r(110) = -0.641, p = < 0.001) and item 15<br />

(depressed / discouraged) (UC: r(74) = -0.686, p = < 0.001;CD: r(112) =<br />

-0.653, p = < 0.001).<br />

Fatigue and general well‐being<br />

Although a wider variation was observed than that in other factors, a<br />

strongly significant, anti-proportional correlation was found ( R2 = 0,316,<br />

p < 0.001, Table 4) between the total fatigue score and the GAS score.<br />

Fatigue and pain<br />

Pearson’s correlation coefficient indicated linear correlations of current<br />

pain intensity on the VAS ( R2 = 0.128, p < 0.001, Table 4) with the<br />

total verbal pain score ( R2 = 0.152, p < 0.001, Table 4) and the total<br />

fatigue score. The subjective overall assessment of the pain intensity<br />

caused by the disease indicated that 52.3% of patients who did not<br />

have fatigue classified their pain as low or mild. In contrast, 77.2% of<br />

the patients with extreme fatigue reported that their pain intensity was<br />

distressing or worse (p < 0.001).<br />

Fatigue and laboratory values<br />

Univariate factor analysis of the total fatigue score and laboratory<br />

values is shown in Table 3. No statistical differences were found<br />

regarding anemia, elevated CRP or elevated fecal calprotectin. A total<br />

of 36.1% (61) of participants had anemia. Analysis according to fatigue<br />

indicated no significant difference between groups: 62.3% of the<br />

anemic patients and 63.9% of the non-anemic patients had fatigue (p =<br />

0.437). In addition, the inflammatory values in the blood and stool were<br />

not found to be predictive factors for fatigue (p = 0.057; p = 0.27).<br />

Multivariate analysis<br />

In the multivariate analysis, we stratified by IBD diagnosis and<br />

included all factors that were significant in the univariate analysis as<br />

well as sex and age (Table 5). After controlling for each of the other<br />

variables, sex (p = 0.015), depression (p = 0.002) and quality of life (p<br />

= 0.003) in CD, and age (p = 0.024) and depression (0.02) in UC were<br />

significantly associated with fatigue. Trends were observed for age<br />

(p = 0.057) in CD and for anxiety (p = 0.055) in UC. Unexpectedly, an<br />

antiproportional trend was found for disease activity and fatigue in UC.<br />

All other factors were found to be confounders. The results are shown<br />

in Table 5. Although association with sex was highly significant over<br />

both diagnoses in univariate analysis, no correlation was observed for<br />

UC in regression analysis. In contrast, age was not significant in the<br />

univariate analysis but was significant in regression analysis for CD.<br />

Discussion<br />

Fatigue in patients with IBD remains poorly understood. This crosssectional<br />

study of 189 patients with IBD, aimed to investigate the<br />

prevalence of fatigue, explore its associations with various factors, and<br />

identify important implications for clinical practice. It indicated three<br />

major findings. First, fatigue was highly prevalent: 63.5% of patients<br />

with IBD experienced either fatigue or severe fatigue, regardless of<br />

disease type and activity. Second, to address fatigue, physicians<br />

should look beyond laboratory parameters, because anemia and<br />

lab values which reflect disease activity do not reliably correlate with<br />

fatigue. Third, the diagnostic workup of patients presenting with fatigue<br />

should include screening for depression.<br />

In this study, the observed prevalence of fatigue in patients with IBD<br />

was 63.5% (51.3% with fatigue and 12.3% with severe fatigue)—a<br />

percentage four times higher than that reported in the general<br />

population [35]. The FAS results in patients with IBD are consistent with<br />

those in previously published studies using other fatigue instruments<br />

[5, 6, 19, 36]. In line with findings from previous studies, no differences<br />

between the type of IBD and the occurrence or severity of fatigue were<br />

found [15, 16, 19, 22]. The prevalence of fatigue in patients with IBD in<br />

remission was approximately 50% in our study. Nearly all past studies<br />

have reported that a large number of patients in remission still have<br />

fatigue [4, 13, 15]. Therefore, the fatigue response may be independent<br />

of the degree of intestinal inflammation and may be signaled through<br />

other pathways [13].<br />

Management of fatigue in patients with IBD is challenging. If following<br />

guidelines, laboratory testing for, and supplementing with, vitamin B12,<br />

folate and iron are recommended [37].<br />

Anemia is one of the most frequent complications in patients with IBD<br />

[38, 39]. However, in this study, no association was found between<br />

the presence of anemia and fatigue, as 62.3% of the anemic patients<br />

and 63.9% of the non-anemic patients experienced fatigue. Conflicting<br />

results have been reported [2, 8, 9, 37, 40], but, the majority of<br />

18


FEATURE<br />

studies are in agreement with our findings [13, 15, 19, 22, 41–43].<br />

Vitamin B12, folate and iron levels were not assessed in the current<br />

study, thus, subclinical deficiencies may have an impact. Likewise, a<br />

recent randomized controlled trial demonstrated the effectiveness of<br />

high-dose oral thiamine for the treatment of fatigue in patients with<br />

quiescent IBD [44].<br />

The influence of disease activity on fatigue development has been<br />

investigated in previous studies. Most studies that performed multivariate<br />

regression analysis, to account for possible confounders, did not find an<br />

association between fatigue and disease activity, in accordance with our<br />

data [2, 13, 15, 19, 45, 46]. Among the studies that found associations<br />

for IBD [4, 17, 42, 47] or specific subtypes of IBD [16, 48], two studies<br />

did not correct for psychosomatic dimensions (e.g., pain, anxiety and<br />

depression) [17, 42], and those that did correct have found conflicting<br />

results [4] or no correlation with disease activity after multivariate analysis<br />

[47, 48]. Studies that have used the same activity scores (HBI and partial<br />

Mayo) have come to the same conclusion that disease activity alone is<br />

not the main driver of fatigue [13, 15].<br />

In agreement with the observations of clinical scores, fecal<br />

calprotectin, which correlates well with disease activity [34], and CRP<br />

elevation did not show a correlation with fatigue in both CD or UC in<br />

this study. This finding is consistent with previous studies [16, 22, 42,<br />

47]. Huppertz-Hauss et al. and Bager et al. have described that the<br />

perceived disease’s symptom burden, rather than its biochemical<br />

markers, correlates with fatigue [16, 42]. Further analysis of the IBDQ<br />

results in this study revealed that patient-reported items indicating<br />

active disease, such as rectal bleeding (UC/CD), loose stools (UC), and<br />

increased stool frequency (UC) did not show a significant correlation<br />

with the level of fatigue. However, items related to disease burden,<br />

such as disrupted / restricted participation in activities, embarrassment<br />

and emotional aspects did correlate significantly. The findings of<br />

Jelsness-Jorgensen et al. indicating that patients with inactive IBD<br />

and additional irritable bowel syndrome have higher fatigue levels than<br />

those without, underlines the influence of perceived burden rather than<br />

actual inflammatory activity [49].<br />

In our study, depression, measured by the HADS-D, showed<br />

the strongest associations with fatigue in both CD and UC in the<br />

multivariate analysis. Similar results have been reported by previous<br />

studies [7, 13, 15, 46, 50, 51]. Depression and fatigue have common<br />

behavioral, affective and cognitive characteristics; furthermore, they<br />

may even share similar causal pathways [7, 46, 51]. Truyens et al.<br />

[52] suspected fatigue to be a symptom of underlying undetected<br />

depression. This hypothesis was supported by our study, in which<br />

100% of patients with conspicuous values on the HADS-D scale<br />

had fatigue. The connection between depression and IBD through<br />

the gut-brain-axis has been shown to be bidirectional. Severe IBD<br />

has been shown to impact psychology and is associated with newonset<br />

depression [53]. Conversely, depression can negatively affect<br />

the course of IBD [52, 54–56]. Hence identifying and appropriately<br />

addressing depression in patients with IBD are crucial. Patients<br />

reporting symptoms of fatigue should be screened for concomitant<br />

depression, particularly when the common fatigue work-up is<br />

unremarkable.<br />

Despite strong correlations in the univariate analysis, the variables<br />

anxiety, current well-being and pain did not remain significant in the<br />

multivariate analysis and were found to be confounders. Nevertheless,<br />

they should not be completely disregarded in the assessment of<br />

fatigue, regarding anxiety there was a tendency for correlation in the<br />

multivariate analysis in UC. Agerelated effects on fatigue exhibited a<br />

weak and inconsistent correlation, possibly stemming from variations in<br />

age and gender distribution between the two disease types [42].<br />

As in any scientific investigation, this study has several limitations. The<br />

participants in this study were patients from the outpatient department<br />

of a tertiary referral center. This may limit the generalizability of the<br />

findings to the entire IBD population, e.g., the level of fatigue among<br />

outpatients in an oncological study was observed to be higher<br />

compared to that of inpatients [57]. Laboratory values were recorded<br />

not numerically but only nominally (increased or not increased). In<br />

addition, the data were laboratory values from a maximum of 4 weeks<br />

before or after completion of the questionnaires, thus potentially<br />

leading to inaccuracy, given that therapeutic interventions or flares<br />

might have occurred during the period between sample collection<br />

and assessment of fatigue. Moreover, most surveyed patients were in<br />

remission (52%) or had only mild symptoms (25.7% mild disease).<br />

The FAS, which has been shown to be a reliable instrument to assess<br />

fatigue [26, 27], is unidimensional, thereby hindering direct comparison<br />

with previous IBD studies that have used other (multidimensional)<br />

fatigue scores. The strengths of the study include the broad<br />

assessment of possible factors influencing fatigue through a broad set<br />

of validated questionnaires as well as clinical and paraclinical data in<br />

almost 200 patients with IBD.<br />

Conclusions<br />

In conclusion, we demonstrated that fatigue is burdensome and highly<br />

prevalent in patients with IBD. Fatigue should receive attention in<br />

patients with active disease as well as disease in remission, because it<br />

did not significantly correlate with anemia or disease activity. Thus, we<br />

recommend implementing an easy to fill-out fatigue survey, such as the<br />

FAS which takes about 2 min to complete, in daily practice. The strong<br />

associations with depression highlight the importance of investigating<br />

and addressing possible underlying sub-clinical depression in patients<br />

reporting fatigue symptoms.<br />

Abbreviations<br />

CD Crohn’s disease<br />

CRP C-reactive protein<br />

FAS Fatigue Assessment Scale<br />

GAS Global Assessment Scale<br />

HADS Hospital Anxiety and Depression Scale<br />

Hb Hemoglobin<br />

HBI Harvey-Bradshaw Index<br />

HRQoL Health related quality of life IBD Inflammatory bowel disease<br />

IBDQ Inflammatory Bowel Disease Questionnaire p<br />

Mayo Partial Mayo Score<br />

UC Ulcerative colitis<br />

VAS Visual analogue scale<br />

Supplementary Information<br />

The online version contains supplementary material available at<br />

https://doi.org/10.1186/s12876-023-02906-0.<br />

Additional file 1. Correlation between IBDQ items / domains and the<br />

total fatigue score by PearsonÅLs correlation coefficient.<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

19


FEATURE<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

Acknowledgements<br />

We wish to thank all the IBD patients for completing the questionnaires.<br />

We thank Dr.-Ing., M.Sc. Heike Hoyer and Jana Ziegler (both: Institute of<br />

Medical Statistics, Computer and Data Sciences, University Clinic Jena,<br />

Germany) for support with data analysis.<br />

Authors’ contributions<br />

VU and PCG have made substantial contributions to the conception or<br />

design of the work, the acquisition, analysis and interpretation of data for<br />

the work. They drafted the work. AS has made substantial contributions<br />

to the conception or design of the work. He revised the work critically<br />

for important intellectual content. All authors gave final approval of the<br />

version to be published and agreed to be accountable for all aspects of<br />

the work in ensuring that questions related to the accuracy or integrity of<br />

any part of the work are appropriately investigated and resolved.<br />

Funding<br />

Open Access funding enabled and organized by Projekt DEAL. No<br />

funding was sourced for this project.<br />

Availability of data and materials<br />

The datasets used and analysed during the current study are available<br />

from the corresponding author on reasonable request.<br />

Declarations<br />

Ethics approval and consent to participate<br />

Ethical approval was granted by the Ethics Committee of the Jena<br />

University Hospital, Jena, Germany (5530–05/18), and all patients<br />

provided signed informed consent for participation in the study,<br />

according to the Declaration of Helsinki.<br />

Consent for publication<br />

Not applicable.<br />

Competing interests<br />

VU reports no competing interests. AS reports research funding from<br />

AbbVie and Celltrion and has received lecture fees from AbbVie, Amgen,<br />

Astellas, Biogen, Celltrion, Institut Allergosan, Janssen, Falk Foundation,<br />

Ferring, MSD, Recordati Pharma, Streamed-Up, and Takeda, and<br />

consulting fees from AbbVie, Astellas, Amgen, Biogen, CLS Behring,<br />

Consal, Galapagos, Hexal, Janssen, MSD, Norgine, Pfizer Pharma,<br />

Takeda, Pharmacosmos, and Tillots Pharma. PCG obtained consulting<br />

fees from Janssen and Takeda and lecture fees and from AbbVie,<br />

Janssen, Pfizer, Falk, and Takeda.<br />

Received: 12 March <strong>2023</strong> Accepted: 25 July <strong>2023</strong><br />

Published online: 22 August <strong>2023</strong><br />

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Springer Nature remains neutral with regard to jurisdictional claims in<br />

published maps and institutional affiliations.<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

21


NEWS<br />

“We know that this can also have a<br />

detrimental effect on their mental wellbeing.<br />

“The rates of microscopic colitis are<br />

increasing and are likely to grow further as<br />

the population ages, so it’s crucial that we<br />

identify risk factors, provide specific training<br />

for healthcare providers, continue to raise<br />

awareness and invest in research to improve<br />

diagnosis and treatments.”<br />

Chris Probert, professor of gastroenterology<br />

at the University of Liverpool, added:<br />

“Undiagnosed microscopic colitis can cause<br />

years of unnecessary suffering.<br />

“The diarrhoea symptoms tend to be<br />

very severe and house-limiting, leading to<br />

considerable distress for patients.<br />

Concern over undiagnosed<br />

cases of severe bowel<br />

condition<br />

Ella Pickover, PA Health Correspondent<br />

Microscopic colitis is a debilitating condition<br />

which leads to inflammation of the large<br />

bowel, it can cause symptoms including<br />

persistent watery diarrhoea, stomach pain,<br />

fatigue, urgency to go to the toilet and waking<br />

in the night to empty the bowel.<br />

“It’s not clear why cases of the condition are<br />

on the increase but it is likely to be due to a<br />

mixture of increased awareness of symptoms<br />

leading to more diagnoses and environmental<br />

factors such as a potential side effect of<br />

common prescription drugs such as some<br />

antidepressants.<br />

More must be done to stop people suffering<br />

unnecessarily due to a lack of awareness<br />

about a severe bowel condition, a charity<br />

has warned.<br />

Some 17,000 people are diagnosed with<br />

microscopic colitis each year in the UK but<br />

Guts UK believes the real figure could be a lot<br />

higher due to high rates of misdiagnosis and<br />

the complex way the condition is detected.<br />

Unlike other inflammatory bowel diseases,<br />

microscopic colitis cannot be seen on a<br />

camera and requires a tissue sample to be<br />

taken from the bowel and examined under<br />

a microscope.<br />

Because this step is not always completed,<br />

many are left undiagnosed, Guts UK said.<br />

Experts have also suggested that people<br />

aren’t seeking help for symptoms because<br />

they are embarrassed or, if they do, they’re<br />

often misdiagnosed with irritable bowel<br />

syndrome (IBS).<br />

The charity said that once diagnosed, there<br />

is an effective treatment for most people<br />

as it called for more to be done to improve<br />

diagnosis rates.<br />

A previous study has shown that one-inthree<br />

patients with the condition were initially<br />

diagnosed with irritable bowel syndrome.<br />

The charity said that previous estimates have<br />

suggested that some 67,000 people could be<br />

living with the condition in the UK, with more<br />

women thought be affected.<br />

It said that, despite misdiagnoses, cases<br />

are on the rise – in the UK incidence rate of<br />

microscopic colitis in 2016 was twice that<br />

observed in 2009.<br />

“It’s terribly sad that thousands of people<br />

are suffering with the debilitating symptoms<br />

of microscopic colitis,” said Julie Harrington,<br />

chief executive of Guts UK.<br />

“Most people with the condition can be easily<br />

treated with a course of gut-specific steroids<br />

or with symptom-relieving medicines but<br />

getting a diagnosis is the first, essential step.<br />

“People living with the condition but without<br />

the benefit of a correct diagnosis and effective<br />

treatments often can often feel very isolated<br />

due to the urgent nature of their symptoms<br />

and their need to be near to toilet facilities at<br />

all times.<br />

“The good news is that effective treatments<br />

are available so people experiencing<br />

symptoms could benefit enormously by<br />

talking with their GP.”<br />

One women, known only as Victoria, age<br />

33 from London, was diagnosed with<br />

microscopic colitis last year.<br />

“I spent 12 years living with undiagnosed<br />

microscopic colitis,” she said.<br />

“On my worst days, I was going to the toilet<br />

30 to 40 times per day and suffered from<br />

awful stomach cramps.<br />

“I ended up becoming agoraphobic because I<br />

was so distressed. I went to the doctor again<br />

and again but it took me all these years to get<br />

a correct diagnosis. I even went to A&E but<br />

was told it was ‘just IBS’ and I was sent home<br />

with no treatment plan.<br />

“The treatment I have received after getting<br />

my diagnosis has changed my life. I feel like<br />

I’ve regained some semblance of normal.”<br />

Guts UK has created a new resource for<br />

patients to find out more about the condition.<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

23


NEWS<br />

Severe bowel condition on<br />

the rise in the UK<br />

Many people suffer with the condition for years<br />

but the correct diagnosis and treatment can<br />

make a huge difference. [8]<br />

continue to raise awareness and invest in<br />

research to improve diagnosis and treatments.”<br />

Professor Chris Probert, Professor of<br />

• Resource for patients published by the national<br />

charity Guts UK highlights the growing number<br />

of microscopic colitis cases in the UK.<br />

Victoria, age 33 from London, was diagnosed<br />

with microscopic colitis last year. She said:<br />

<strong>Gastroenterology</strong> at the University of<br />

Liverpool said:<br />

• The charity has raised concerns about the<br />

number of people suffering with a misdiagnosis<br />

or living with undiagnosed and debilitating<br />

symptoms.<br />

• 17,000 new cases are being diagnosed each<br />

year, but the real number could be a lot higher.<br />

Experts have raised concerns about the<br />

number of people suffering with undiagnosed<br />

microscopic colitis, a debilitating bowel condition<br />

thought to affect thousands of adults in the UK.<br />

The national charity Guts UK has published a<br />

resource for patients during Microscopic Colitis<br />

Awareness Week to raise awareness of the<br />

disease and is calling for more research into<br />

prevention, faster diagnoses and developments<br />

in treatments.<br />

“I spent 12 years living with undiagnosed<br />

microscopic colitis. On my worst days, I was going<br />

to the toilet 30 to 40 times per day and suffered<br />

from awful stomach cramps. I ended up becoming<br />

agoraphobic because I was so distressed. I went<br />

to the doctor again and again but it took me all<br />

these years to get a correct diagnosis. I even went<br />

to A&E but was told it was ‘just IBS’ and I was sent<br />

home with no treatment plan.<br />

“By 2022 I became scared of eating in case<br />

it triggered symptoms and my flare ups were<br />

becoming more frequent. I felt more tired than I’d<br />

ever felt in my life and completely hopeless. I was<br />

also trying to parent my baby son while living with<br />

the condition.<br />

“The treatment I have received after getting my<br />

diagnosis has changed my life. I feel like I’ve<br />

regained some semblance of normal.”<br />

“Undiagnosed microscopic colitis can cause years<br />

of unnecessary suffering. The diarrhoea symptoms<br />

tend to be very severe and houselimiting leading to<br />

considerable distress for patients.<br />

“It’s not clear why cases of the condition are on<br />

the increase but it is likely to be due to a mixture<br />

of increased awareness of symptoms leading to<br />

more diagnoses and environmental factors such<br />

as a potential side effect of common prescription<br />

drugs such as some antidepressants.<br />

“The good news is that effective treatments are<br />

available so people experiencing symptoms could<br />

benefit enormously by talking with their GP.”<br />

Resources published in March 2022 by Guts UK<br />

to raise awareness of microscopic colitis showed<br />

that women are 700% more likely than men to<br />

suffer with the condition.<br />

Microscopic colitis is an inflammation of the large<br />

intestine (bowel) that causes persistent, frequent<br />

and watery diarrhoea (throughout the day and<br />

night), stomach pain, fatigue, faecal incontinence<br />

and weight loss. It is frequently misdiagnosed<br />

and the prevalence of the condition is higher than<br />

previously thought. [1]<br />

Microscopic colitis is named because, unlike<br />

other inflammatory bowel diseases, like Crohn’s<br />

disease or ulcerative colitis, it can’t be diagnosed<br />

with a colonoscopy alone and a sample of tissue<br />

taken from the bowel must be examined under a<br />

microscope to identify the condition. Because of<br />

this, the disease is often misdiagnosed.<br />

The causes of microscopic colitis are still unclear.<br />

As it is a relatively new disease (first described<br />

in 1976) it has led to a presumption that it is<br />

environmental as opposed to genetic factors that<br />

are responsible for its occurrence.<br />

For more information visit gutscharity.org.uk<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

Scientists estimate that around 67,000 people<br />

are living with microscopic colitis in the UK or at<br />

least 1 in 1,000 adults.[2][3] 17,000 new cases<br />

are being diagnosed each year, but the real<br />

number could be a lot higher because it’s often<br />

underreported and misdiagnosed.[4]<br />

A 2012 study showed that one in three patients<br />

with microscopic colitis were initially incorrectly<br />

diagnosed with Irritable Bowel Syndrome (IBS)<br />

and “a large, hidden burden of undiagnosed and<br />

untreated microscopic colitis likely exists in the<br />

UK population owing to systematic misdiagnosis<br />

of microscopic colitis as IBS.”[5][6]<br />

Despite the missed diagnoses, cases of<br />

microscopic colitis are on the rise globally. The<br />

UK incidence rate of microscopic colitis in 2016<br />

was twice that observed in 2009.[7]<br />

Microscopic colitis is a leading cause of<br />

diarrhoea in older adults and it can have a<br />

devastating impact on a person’s quality of life.<br />

Julie Harrington, CEO of Guts UK, said:<br />

“It’s terribly sad that thousands of people<br />

are suffering with the debilitating symptoms<br />

of microscopic colitis. Most people with the<br />

condition can be easily treated with a course of<br />

gut-specific steroids or with symptom-relieving<br />

medicines but getting a diagnosis is the first,<br />

essential step.<br />

“People living with the condition but without<br />

the benefit of a correct diagnosis and effective<br />

treatments often can often feel very isolated due<br />

to the urgent nature of their symptoms and their<br />

need to be near to toilet facilities at all times. We<br />

know that this can also have a detrimental effect<br />

on their mental wellbeing.<br />

“The rates of microscopic colitis are increasing<br />

and are likely to grow further as the population<br />

ages, so it’s crucial that we identify risk factors,<br />

provide specific training for healthcare providers,<br />

#MicroscopicColitisAwareness<br />

[1] Undiagnosed microscopic colitis: a hidden cause<br />

of chronic diarrhoea and a frequently missed<br />

treatment opportunity: https://fg.bmj.com/<br />

content/11/3/228<br />

[2] Aprox. 67,000 people are living with Microscopic<br />

Colitis in the UK - around 58,600 women and<br />

8,400 men.<br />

[3] Microscopic colitis includes two related<br />

inflammatory bowel disorders, lymphocytic<br />

colitis and collagenous colitis that have a<br />

combined prevalence of 103 cases per 100 000<br />

population: May 2019.<br />

[4] https://www.crohnsandcolitis.org.uk/aboutcrohns-and-colitis/publications/microscopiccolitis<br />

[5] https://www.ncbi.nlm.nih.gov/pmc/articles/<br />

PMC3484793/<br />

[6] https://drive.google.com/file/d/1XF-<br />

FoJM3wGeoO1krPzh-aQiACXSYwPSf/<br />

view?usp=sharing<br />

[7] https://gut.bmj.com/content/66/Suppl_2/A156.1<br />

[8] https://www.ncbi.nlm.nih.gov/pmc/articles/<br />

PMC8776530/<br />

[9] 87.5% of people suffering with the condition are<br />

female - most of whom are diagnosed between<br />

the ages of 50 and 70.<br />

24


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NEWS<br />

Inflammatory bowel disease<br />

treatments reach inflection<br />

point requiring active<br />

comparators, says GlobalData<br />

At Digestive Disease Week (DDW)<br />

<strong>2023</strong>, a comment was made following a<br />

presentation discussing the preliminary<br />

induction findings from GlobalData, a<br />

leading data and analytics company.<br />

The attendant continued by pointing out that<br />

GUS was shown to only effect remission in less<br />

than a quarter of the treated patients (22.5%),<br />

with a moderate benefit over placebo of only<br />

approximately 12%. The commenter concluded<br />

the argument with the observation that GUS and<br />

many other inflammatory bowel disease (IBD)<br />

therapies do not meet the historical therapeutic<br />

standards, referencing a recent meta-analysis<br />

study that showed that treatments generally<br />

achieve a 20% delta over placebo.<br />

Adeleke Badejo, Senior Analyst – Immunology<br />

at GlobalData, comments: “At the crux of this<br />

line of thought is a lack of evidence to support the<br />

market narrative and messaging of high-quality<br />

current and upcoming IBD therapies, and a need<br />

for better data.”<br />

Observed from recent interviews of key opinion<br />

leaders (KOLs) within IBD conducted by<br />

GlobalData, the unmet need for more evidence<br />

to define the most efficacious therapy in the<br />

field has been echoed repeatedly. One such<br />

thought leader acknowledged the current status<br />

quo with companies being able to “get away, so<br />

to speak, in the IBD field with these placebocontrolled<br />

trials”.<br />

Adding that the sole use of placebo is not the<br />

norm with other indications. “I think you see more<br />

comparative effectiveness trials in some of the<br />

other fields, certainly in oncology… it’s always<br />

the standard of care versus the new thing”.<br />

Addressing this situation, not only improves the<br />

quality of care for the IBD patient population,<br />

but it also would benefit companies in a quickly<br />

evolving and expanding market.<br />

Badejo continues: “The significance of<br />

addressing this unmet need is of increased<br />

importance in light of recent bets within IBD and<br />

immunology through mergers and acquisitions,<br />

such as the purchase of Prometheus<br />

Biosciences by Dice Therapeutics.”<br />

In addition to the effect these strategic<br />

transactions will have on the market in the coming<br />

years, long-established agents such as Humira<br />

and Stelara are transitioning to legacy assets,<br />

providing the opportunity for the next generation<br />

of treatments to capture significant market share.<br />

The current situation would be best addressed<br />

through clinical asset evaluation through trials<br />

with active comparators, but of the eight latestage<br />

pipeline agents at the beginning of this<br />

year, only Lilly’s mirikizumab and AstraZeneca’s<br />

brazikumab were being evaluated against<br />

active comparators (ustekinumab and<br />

adalimumab respectively), with the former<br />

program ending following assessment of the<br />

competitive landscape.<br />

Badejo concludes: “The apparent risk with<br />

higher probability of failure associated with<br />

incorporating active comparators during therapy<br />

development is known, but the benefit in<br />

establishing confidence with decision makers<br />

should not be overlooked.”<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

26


COMPANY NEWS<br />

A New Portal To Ef-FITciency:<br />

Introducing The<br />

Alpha Portal (TAP) by Alpha<br />

Laboratories<br />

The Faecal Immunochemical Test (FIT)<br />

has revolutionised the colorectal cancer<br />

referral pathway with its quick and<br />

user-friendly nature, making it an easily<br />

integrated test for efficient patient triaging.<br />

However, the valuable benefits of FIT<br />

have brought forth logistical challenges,<br />

primarily concerning sample collection<br />

kit distribution to healthcare providers<br />

and patients. The increasing demand for<br />

this essential test is rapidly outpacing the<br />

current capacity.<br />

To tackle these challenges head-on, Alpha<br />

Laboratories has collaborated with FIT users<br />

to introduce the Alpha Portal (TAP), marking<br />

the next phase in FIT evolution. TAP is a<br />

cutting-edge solution designed to streamline<br />

and manage the logistics associated with<br />

the Faecal Immunochemical Test, providing<br />

a scalable and efficient system to meet<br />

the surging demand. Already proving its<br />

effectiveness, Southmead Hospital in Bristol<br />

has experienced significant improvements in<br />

its FIT service following the implementation<br />

of TAP.<br />

Key features of the Alpha Portal include:<br />

FIT-KIT Stock Management: Offering a<br />

snapshot of FIT-KIT stock levels, lot and<br />

expiry dates, and real-time tracking to ensure<br />

a continuous and seamless supply.<br />

Print-Ready Documents: Providing<br />

healthcare providers with easily accessible<br />

and print-ready documents detailing kit<br />

components and product descriptions.<br />

Traceable Ordering System: Implementing<br />

a sophisticated ordering system to deliver<br />

FIT-KITs to any location in the UK, ensuring<br />

prompt and reliable distribution.<br />

Order Reports: Generating comprehensive<br />

order reports that highlight demand at each<br />

site and ordering frequency, allowing for<br />

better inventory management.<br />

The Alpha Portal has been met with<br />

enthusiasm and praise from various<br />

healthcare facilities across the UK,<br />

significantly reducing unnecessary workload<br />

and enhancing the scalability of the FIT<br />

service. As Alpha Laboratories remains<br />

committed to delivering top-notch solutions, it<br />

has exciting plans for additional offerings from<br />

TAP in the near future.<br />

In conclusion, the Alpha Portal (TAP) is<br />

a game-changing tool for managing the<br />

logistical challenges associated with the<br />

Faecal Immunochemical Test (FIT). It<br />

provides an efficient and reliable means of<br />

tracking, ordering, and distributing FIT-KIT<br />

components, enabling healthcare providers<br />

to meet the soaring demand for this crucial<br />

test. By adopting TAP, healthcare facilities<br />

can optimize their FIT services and focus on<br />

providing timely and effective care to patients.<br />

Please visit www.faecal-immunochemicaltest.co.uk/TAP<br />

for further information or<br />

contact Alpha Laboratories on 0800 38 77 32<br />

or email marketing@alphalabs.co.uk<br />

Microbiome characterisation<br />

ensures success in faecal<br />

microbiota transplantation<br />

Graham Johnson, Managing Director,<br />

BIOHIT Healthcare.<br />

Faecal microbiota transplantation (FMT)<br />

is becoming a more widespread treatment<br />

for dysbiosis-associated conditions, in<br />

particular, for gastrointestinal disorders,<br />

and its use was further endorsed<br />

recently when, in 2022, the National<br />

Institute for Health and Care Excellence<br />

(NICE) approved it for treating recurrent<br />

Clostridium difficile infections.[1]<br />

However, several randomized controlled<br />

trials investigating FMT in irritable bowel<br />

syndrome (IBS) patients have revealed<br />

huge variability in treatment response.<br />

[2] These contradictory findings may be<br />

attributable to a lack of standardisation<br />

in various aspects of the trial protocol<br />

design, one of which is donor selection<br />

criteria.[3] At the same time, there has<br />

been a rising tendency to recruit ‘superdonors’<br />

– favourable both in terms<br />

of their microbial diversity and stool<br />

composition – with the aim of ensuring<br />

positive outcomes for recipient patients.<br />

[4, 5] The gut microbiota of these donors<br />

is currently not always characterised, but<br />

some advocates of FMT are beginning to<br />

suggest that this may be more valuable<br />

than simple clinical screening when it<br />

comes to matching recipients to donors,<br />

especially with the innovative diagnostic<br />

tools that are now available.[6] Microbial<br />

profiling undoubtedly provides key<br />

information, such as the abundance and<br />

diversity of bacteria in the gut – as well as<br />

a measure of dysbiosis in patients – and<br />

applying this approach across the board<br />

as a measure of standardisation could<br />

help to refine therapeutic FMT strategies<br />

and lead to more consistent study results<br />

with favourable patient outcomes.[7]<br />

Purposeful protocol design<br />

This is certainly the strategy chosen by Magdy<br />

El-Salhy, Professor of <strong>Gastroenterology</strong><br />

and Hepatology at the University of Bergen,<br />

whose research team recently conducted a<br />

clinical trial to determine the efficacy of FMT<br />

for IBS patients.[8] The study found that FMT<br />

is an effective therapy for IBS, with up to 89.1<br />

% of patients responding to treatment, and<br />

around half of all patients experiencing clinical<br />

improvements in abdominal symptoms,<br />

fatigue and quality of life. However, Magdy is<br />

convinced that protocol design was key to<br />

ensuring the validity of the study results. There<br />

were five important factors: the super-donors<br />

were screened against set criteria; there<br />

was frequent faecal analysis of the donor to<br />

monitor microbiome stability; the fresh donor<br />

faeces were immediately frozen; the sample<br />

was mixed manually prior to administration;<br />

and the donor material was administered<br />

by gastroscope directly into the recipient’s<br />

duodenum.<br />

The right tool for the job<br />

On top of this, the GA-map ® Dysbiosis<br />

Test (GA-map ® Test) – a gut microbiota<br />

DNA-based platform that identifies and<br />

characterises dysbiosis – was used<br />

throughout the trial, as Magdy explained:<br />

“The GA map ® Test was fundamental to the<br />

analytical element of our trial; we used it to<br />

profile the faecal samples from the donor and<br />

to evaluate the intestinal bacterial profiles of<br />

patients following transplantation.” GA-map ®<br />

Test assigns each sample with an index that<br />

ranges from 1 for ‘normobiosis’ to any score<br />

greater than 2 to represent an increasing<br />

degree of dysbiosis. Samples are then<br />

cross-indexed with an additional value that<br />

represents the abundance of present species<br />

compared to the reference population.<br />

Indexing in this manner refines the definition<br />

of dysbiosis and multiple FMT studies have<br />

correlated the GA-map ® Test index with<br />

effectiveness of therapeutic intervention.[9-12]<br />

Standardisation for success<br />

The trial protocol included faecal analysis of<br />

the super-donor at the start of the study to<br />

ensure that they had normal gut microbiota,<br />

and then at three monthly intervals<br />

throughout the year to confirm stability of<br />

their microbiome. Christina Casèn, Senior<br />

Vice President, Clinical and Medical Affairs at<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

27


COMPANY NEWS<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

Genetic Analysis AS, said: “A standardised<br />

and validated test that could be conducted<br />

in situ was vital for this study as it involved<br />

repeated sampling and measurements of<br />

the donor. Performing analyses with the<br />

GA-map ® Test allowed the trial clinicians to<br />

compare results from different time periods<br />

instantaneously and evaluate FMT efficacy<br />

on site.”<br />

Characterisation to further understanding<br />

The study conducted by Magdy and his<br />

team confirmed that the outcome of FMT<br />

in IBS patients is donor dependent, and<br />

demonstrated that standardisation of key<br />

aspects of the trial protocol is critical. A donor<br />

needs to be well defined with both a normal<br />

dysbiosis index and a favourable specific<br />

microbial signature, and using dysbiosis<br />

testing platforms for characterisation can<br />

reduce variability in clinical response and<br />

ultimately ensure success of the FMT method.<br />

When clinicians are able to perform DNAbased<br />

faecal analysis themselves during<br />

trials – without needing to send samples to an<br />

external sequencing laboratory – they benefit<br />

from instantaneous information that guides<br />

FMT as an effective therapeutic intervention.<br />

References<br />

[1] NICE recommends transplant with<br />

good bacteria taken from poo to resolve<br />

recurrent Clostridium difficile infections |<br />

News | News | NICE, https://www.nice.<br />

org.uk/news/nice-recommends-faecalmicrobiota-transplant-for-recurrentclostridioides-difficile-infection<br />

(accessed<br />

16 January <strong>2023</strong>).<br />

[2] Cammarota G, Ianiro G, Tilg H, et al.<br />

European consensus conference on<br />

faecal microbiota transplantation in<br />

clinical practice. Gut 2017; 66: 569–580.<br />

[3] El-Salhy M, Hausken T, Hatlebakk<br />

JG. Current status of fecal microbiota<br />

transplantation for irritable bowel<br />

syndrome. Neurogastroenterology<br />

and Motility; 33. Epub ahead of print<br />

1 November 2021. DOI: 10.1111/<br />

NMO.14157.<br />

[4] Koren O, Fiorucci S, O’sullivan JM,<br />

et al. The Super-Donor Phenomenon<br />

in Fecal Microbiota Transplantation.<br />

Frontiers in Cellular and Infection<br />

Microbiology | www.frontiersin.org; 1.<br />

Epub ahead of print 2019. DOI: 10.3389/<br />

fcimb.2019.00002.<br />

[5] Moayyedi P, Surette MG, Kim PT, et<br />

al. Fecal Microbiota Transplantation<br />

Induces Remission in Patients With<br />

Active Ulcerative Colitis in a Randomized<br />

Controlled Trial. <strong>Gastroenterology</strong> 2015;<br />

149: 102-109.e6.<br />

[6] Allegretti JR, Mullish BH, Kelly C, et<br />

al. The evolution of the use of faecal<br />

microbiota transplantation and emerging<br />

therapeutic indications. The Lancet 2019;<br />

394: 420–431.<br />

[7] Ianiro G, Puncochár M, Karcher N, et<br />

al. Variability of strain engraftment and<br />

predictability of microbiome composition<br />

after fecal microbiota transplantation<br />

across different diseases. Nature<br />

Medicine 2022 28:9 2022; 28: 1913–<br />

1923.<br />

[8] El-Salhy M, Gunnar Hatlebakk J,<br />

Kristoffersen AB, et al. Gut microbiota<br />

Efficacy of faecal microbiota<br />

transplantation for patients with irritable<br />

bowel syndrome in a randomised,<br />

double-blind, placebo-controlled study.<br />

Gut 2020; 69: 859–867.<br />

[9] Wei S, Bahl MI, Dahl Baunwall SM, et<br />

al. Determining Gut Microbial Dysbiosis:<br />

a Review of Applied Indexes for<br />

Assessment of Intestinal Microbiota<br />

Imbalances. Epub ahead of print 2021.<br />

DOI: 10.1128/AEM.00395-21.<br />

[10] El-Salhy M, Hausken T, Hatlebakk JG.<br />

Increasing the Dose and/or Repeating<br />

Faecal Microbiota Transplantation (FMT)<br />

Increases the Response in Patients with<br />

Irritable Bowel Syndrome (IBS). DOI:<br />

10.3390/nu11061415.<br />

[11] Mazzawi T, Lied GA, Sangnes DA,<br />

et al. The kinetics of gut microbial<br />

community composition in patients with<br />

irritable bowel syndrome following fecal<br />

microbiota transplantation. PLoS One<br />

2018; 13: e0194904.<br />

[12] El-Salhy M, Hatlebakk JG, Gilja OH,<br />

et al. Efficacy of faecal microbiota<br />

transplantation for patients with irritable<br />

bowel syndrome in a randomised,<br />

double-blind, placebo-controlled study.<br />

Gut 2020; 69: 859–867.<br />

Biography<br />

Professor Magdy El-Salhy, BSc, MSc,<br />

MD, PhD is a professor emeritus in the<br />

Department of Clinical Medicine at the<br />

University of Bergen, where he leads the<br />

Neurogastroenterology Section, as well as<br />

being a consultant gastroenterologist in the<br />

Department of <strong>Gastroenterology</strong> at the Stord<br />

Helse Fonna Hospital. Professor El-Salhy has<br />

investigated the gut neuroendocrine system<br />

(NES) and its role in different gastrointestinal<br />

diseases/disorders for almost 40 years,<br />

authoring more than 280 publications,<br />

and is an editorial board member for nine<br />

international journals. His research during the<br />

last 15 years has been devoted to improving<br />

our understanding of the pathophysiology of<br />

IBS, and the development of new methods<br />

for its diagnosis. Professor El-Salhy has been<br />

awarded several prestigious prizes in Egypt,<br />

Sweden and the Republic of Bashkortostan,<br />

as well as from United European<br />

<strong>Gastroenterology</strong>, the European Society of<br />

Neurogastroenterology, and Motility, and The<br />

Rome Foundation.<br />

The 18th Dr Falk Pharma/<br />

Guts UK Awards:<br />

Recognising Dedication,<br />

Enthusiasm & Commitment<br />

in Digestive and Metabolic<br />

Disease<br />

‘The future of GI & Hepatology medicine<br />

& healthcare is in safe hands.’<br />

A trainee doctor researching the role of<br />

the gut microbiome within the potentially<br />

fatal liver condition biliary atresia, a medical<br />

student examining the safety and efficacy of<br />

a capsule form of oesophageal investigation,<br />

a dietitian who instigated a system to provide<br />

patients with oesophago-gastric cancers,<br />

early contact with specialist dietitians, and<br />

a pharmacist who designed and developed<br />

pharmacist-led Inflammatory Bowel Disease<br />

(IBD) clinics to review and assess patients on<br />

biologics.<br />

These are just a few of the talented winners of<br />

the <strong>2023</strong> Dr Falk Pharma UK/Guts UK Charity<br />

Awards, who received their prizes during a<br />

dinner on Tuesday June 20th at the British<br />

Society of <strong>Gastroenterology</strong> (BSG) Annual<br />

Meeting in Liverpool.<br />

Now in its 18th year, celebrating research and<br />

patient care improvement projects carried out<br />

by medical students, junior doctors, specialist<br />

nurses and dietitians, for the first time a<br />

pharmacist award (with two winners) has<br />

been added to the award’s roll call of honour.<br />

With the aim of recognising and further<br />

supporting the increasingly important role of<br />

28


COMPANY NEWS<br />

us with the privilege of learning about<br />

the excellent standards of research and<br />

patient improvement innovations carried<br />

out by young doctors and other dedicated<br />

healthcare professionals within the field of<br />

gastroenterology and hepatology - and <strong>2023</strong><br />

has been no exception.<br />

‘We are delighted too, that this year for the<br />

very first time, our rostrum of winners includes<br />

pharmacists, who play such an important role<br />

in the care of patients with GI or liver diseases.<br />

‘Every one of our winners has shown<br />

passion for their projects, plus the dedication<br />

needed to complete them to an extremely<br />

high standard, often alongside working or<br />

studying full time. They really are the best of<br />

our profession and provide evidence that the<br />

future of GI and Hepatology medicine and<br />

pharmacists within the integrated healthcare<br />

teams, the applications were open to all<br />

pharmacists working in primary or secondary<br />

care and other areas where service redesign<br />

or any project has had a positive impact on<br />

patient outcomes.<br />

The worthy winners were presented with<br />

their awards and prizes by the President<br />

of the BSG, Professor Andrew Veitch and<br />

the Medical Director of Dr Falk Pharma UK,<br />

Dr Riadh Jazwari. Also at the dinner was<br />

the CEO of Guts UK, MS Julie Harrington,<br />

the Managing Director of Dr Falk Pharma<br />

UK, Mr Tony McFadyen, as well as several<br />

internationally renowned members of the<br />

gastroenterology & hepatology community.<br />

Dr Victoria King, Chair of Trustees at Guts UK<br />

comments: ‘For almost two decades, Dr Falk<br />

Pharma UK and Guts UK Charity have been<br />

working hard to maintain the supply of bright,<br />

enquiring minds within gastroenterology,<br />

hepatology and pancreatology.<br />

‘Each year, we come together to recognise<br />

the dedication, enthusiasm and commitment<br />

shown from medical students, doctors,<br />

nurses and dietitians. For the first time in<br />

<strong>2023</strong>, we are delighted to introduce a prize for<br />

pharmacists too. To the winners, our future<br />

Guardians of the Gut – congratulations!’<br />

Medical student Ms Ho Kiu Giselle Ngan<br />

received the Dr Falk Medical Student Essay<br />

Prize for her project entitled A Genomewide<br />

Association Study of Non-alcoholic<br />

Liver Disease in India. Ms Ngan undertook<br />

this research project whilst intercalating for<br />

an iBSc Sciences with Clinical Sciences at<br />

University College London Medical School.<br />

Ms Ngan notes: ‘It is a great honour for me<br />

to receive the Dr Falk Essay Prize. I aspire to<br />

further explore the field of Hepatology and<br />

translational medicine in order to promote<br />

personalised medicine and benefit a wider<br />

population. This award provides me with great<br />

encouragement to pursue a medical career<br />

involving clinical research to help progress<br />

medicine.’<br />

Advance Nurse Practitioner Ms Pearl Avery<br />

has won the Nurse Recognition Award for<br />

the evaluation of her novel role managing<br />

Inflammatory Bowel Disease (IBD) patients in<br />

a primary care setting, reducing unnecessary<br />

referrals to secondary care and reduction<br />

of patients living with long term unresolved<br />

symptoms.<br />

Ms Avery explains: ‘I believe that my project<br />

has provided real benefit to patients and<br />

the GP practice, and I am passionate about<br />

taking this out to GP networks to see if this<br />

model may be adopted by other practices.<br />

‘Winning this award has provided me with<br />

the funding to support this idea, giving me<br />

capacity to work on the analysis which will<br />

allow me to clearly demonstrate the cost<br />

benefit and how the model can fit into primary<br />

care.’<br />

Dr Jazwari comments: ‘Each year, the Dr<br />

Falk Pharma/Guts UK Awards provide<br />

healthcare is in safe hands.’<br />

Brand New Online<br />

Experience from Alpha<br />

Laboratories<br />

New Website for Diagnostic and<br />

Laboratory Solutions.<br />

Alpha Laboratories Ltd. is proud to unveil<br />

its new website, that has been designed to<br />

offer scientists and clinicians easier access to<br />

a wealth of information, across its laboratory<br />

and diagnostics supplies, services and<br />

solutions. Reflecting the company’s growth,<br />

through its customer-focused approach,<br />

it presents an application driven platform,<br />

tailored to meet the needs of both new and<br />

existing customers.<br />

The new website provides a modern, userfriendly<br />

interface that is easy to navigate.<br />

It features a practical search function with<br />

intelligent filtering capabilities that enables<br />

customers to conveniently browse through<br />

both product listings and supplementary<br />

information page options. This helps<br />

customers find what they need easily and<br />

quickly, whether they are planning an<br />

immediate purchase through the efficient<br />

e-commerce platform or are researching<br />

options to be ordered through their own<br />

internal procurement system.<br />

“Our priority has always been to provide the<br />

best possible products and services to our<br />

customers and our new website is just one of<br />

the many ways we continue to support that,”<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

29


COMPANY NEWS<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

says Carole Staniford, Marketing Director.<br />

“We’ve worked hard to create a website that<br />

reflects our commitment to our customers,<br />

and we believe that our new site will make<br />

it easier for them to do business with us,<br />

from direct online transactions to working<br />

in partnership to create bespoke customer<br />

solutions.”<br />

The website features an updated design that<br />

is compatible with all devices and screen<br />

sizes, ensuring that users can access the site<br />

on the go, and from any device. Customers<br />

can easily search for products by product<br />

code, key words, category or applications,<br />

view product specifications, access literature,<br />

videos etc. and even place orders directly<br />

online. For those who need assistance or<br />

have specific queries, the new website also<br />

includes a dedicated customer support<br />

section where they can get in touch with<br />

Alpha Laboratories’ product experts.<br />

Alpha Laboratories Ltd.’s new website<br />

reinforces the company’s position as a topquality<br />

supplier in the market. The website<br />

is live now and ready to explore. For further<br />

information or enquiries, please visit<br />

www.alphalabs.co.uk<br />

Introducing therapeutic<br />

drug monitoring into routine<br />

clinical practice<br />

Dr Christian Selinger, Consultant<br />

Gastroenterologist, Leeds Teaching<br />

Hospitals NHS Trust.<br />

The treatment of inflammatory bowel<br />

disease (IBD) has developed significantly<br />

since the widespread introduction of<br />

biopharmaceuticals. Common biologics<br />

include the TNF-α inhibitors infliximab<br />

(IFX) and adalimumab (ADM), with<br />

vedolizumab and ustekinumab also rapidly<br />

becoming more popular.1 Up to 85 per<br />

cent of patients with IBD have a clinical<br />

response to TNF-α inhibitors, but many<br />

show drug-unresponsiveness either at<br />

instigation of therapy or later on during<br />

the first year of treatment.2 This is often<br />

caused by the development of anti-drug<br />

antibodies (ADAs), which lead to lower<br />

drug trough levels in the bloodstream,<br />

presenting a considerable challenge in<br />

determining the correct course of action<br />

for effective treatment. Therapeutic drug<br />

monitoring (TDM) of trough levels and<br />

ADAs is emerging as a useful tool for<br />

detecting drug unresponsiveness early<br />

on but, despite positive reports of its<br />

reactive use in secondary loss of response<br />

situations,2 uptake has so far been low,<br />

and routine clinical practice for proactive<br />

TDM remains poorly defined. This may<br />

be due, at least in part, to the poor<br />

availability of high sensitivity assays for<br />

trough levels and ADAs, a lack of standard<br />

measurement thresholds, and the potential<br />

expenses incurred by additional testing.2<br />

Pioneers of TDM in gastroenterology<br />

The Leeds Teaching Hospitals NHS Trust<br />

comprises a total of eight hospitals across<br />

West Yorkshire, and provides acute, elective,<br />

secondary and tertiary IBD care to around<br />

4,000 patients. The trust’s gastrointestinal<br />

services are centred at St James’s University<br />

Hospital in Leeds, and are supported by two<br />

additional outpatient endoscopy clinics. The<br />

department applies both medical and surgical<br />

approaches to the prevention, diagnosis and<br />

management of gastrointestinal diseases, and<br />

aims to provide a patient-focussed approach<br />

to treatment.<br />

The trust currently performs TDM of IFX<br />

treatment at 12 and 52 weeks for patients<br />

receiving IV infusions, combining clinical<br />

assessment, medical history, blood<br />

biomarkers – trough and ADA levels – and<br />

imaging to form a complete picture of each<br />

patient’s clinical status. The service uses<br />

the IDKmonitor ® Infliximab Total Anti-drug<br />

Antibody ELISA (BIOHIT HealthCare) to<br />

detect bound and free ADAs in the patient’s<br />

bloodstream. This highly sensitive drugtolerant<br />

assay is particularly useful in<br />

identifying patients with low-titre ADAs, and<br />

supports both the proactive and reactive<br />

investigation of primary non-response and<br />

secondary loss of response to IFX.<br />

This assay has enabled the early detection<br />

of elevated ADA levels in IBD patients<br />

receiving IFX, aiding doctors in making<br />

treatment decisions that may prevent future<br />

lack of response, such as introducing an<br />

immunomodulator or combination therapy, or<br />

optimising dosage to avoid undertreatment.<br />

This pre-emptive TDM approach has allowed<br />

for more effective disease control, leading<br />

to better long-term outcomes for patients<br />

on IFX, and has also helped to reduce<br />

the unnecessary use of drugs, which may<br />

contribute to overall cost savings for the NHS<br />

in the long run.<br />

In addition, the trust sends samples to an<br />

external laboratory for analysis with the<br />

IDKmonitor ® Adalimumab Total Anti-drug<br />

Antibody ELISA, enabling it to perform<br />

reactive TDM for any patient experiencing<br />

loss of response to ADM. Clinicians have<br />

noticed benefits from this analysis, indicating<br />

that proactive monitoring of ADM may also<br />

be advantageous in the future. This approach<br />

could bring other long-lasting benefits to both<br />

the healthcare system and individual patients,<br />

as early observations suggest that therapy<br />

optimisation through TDM has helped to<br />

avoid the need for costly and invasive repeat<br />

imaging procedures, such as colonoscopies<br />

or sigmoidoscopies.<br />

An evidence-based approach to disease<br />

management<br />

TDM performed at the Leeds Teaching<br />

Hospitals NHS Trust has shown much<br />

potential for supporting clinicians in safely<br />

altering TNF-α inhibitor treatment in<br />

individuals showing suboptimal responses,<br />

without negatively affecting patient outcomes<br />

or incurring additional expenses.1,2 Evidence<br />

is also mounting nationally that suggests TDM<br />

for IFX and ADM should be an integral part of<br />

IBD services, although more extensive and<br />

long-term studies are needed to strengthen<br />

this. It will also be important to examine the<br />

role of TDM for subcutaneously delivered IFX<br />

and for other biologics – such as vedolizumab<br />

and ustekinumab – in the coming years,<br />

as there is so far very little data to suggest<br />

whether monitoring would enhance the<br />

outcomes of patients in these care pathways.<br />

Unfortunately, TDM is still not sufficiently<br />

high up on the agenda for many NHS trusts<br />

due to time and financial pressures, and the<br />

case for proactive TDM is not yet compelling<br />

enough to overcome these major barriers and<br />

convince decision makers that widespread<br />

implementation would be a worthwhile<br />

30


COMPANY NEWS<br />

endeavour. However, it is clear that getting the<br />

treatment right from the beginning leads to<br />

better long-term outcomes for IBD patients,<br />

and studies are revealing that bringing TDM<br />

for a range of IBD biologics into routine<br />

practice may have a huge role to play in<br />

supporting this.<br />

References<br />

1. Sagar, R. et al. 2021. Infliximab<br />

Therapeutic Drug Monitoring in<br />

Inflammatory Bowel Disease Virtual<br />

Biologics Clinic Leads to Durable Clinical<br />

Results. Inflamm Intest Dis. 6:132–139,<br />

DOI: 10.1159/000515593.<br />

2. Selinger CP, Lenti M v., Clark T, et al.<br />

2017. Infliximab Therapeutic Drug<br />

Monitoring Changes Clinical Decisions in<br />

a Virtual Biologics Clinic for Inflammatory<br />

Bowel Disease. Inflamm Bowel Dis.<br />

23(12):2083-2088.<br />

Tillotts Pharma and TVM<br />

Capital Life Science<br />

Announce Formation of<br />

Mage Biologics to Develop<br />

Innovative Oral Antibody<br />

Therapy for Ulcerative Colitis<br />

Mage Biologics to develop a monoclonal<br />

antibody targeting ulcerative colitis<br />

early-stage or project-focused company (PFC)<br />

investment for TVM LSI II.<br />

Mage Biologics plans to advance to clinical<br />

proof of concept a novel, orally administered,<br />

humanized monoclonal antibody (mAb)<br />

bioengineered for optimal potency and tissue<br />

penetration. The mAb has been developed<br />

by Tillotts and originated from a discovery<br />

collaboration with Swiss biotech company<br />

Numab Therapeutics. Utilizing Tillotts’<br />

innovative sustained release approach, the<br />

antibody is designed to enable release of the<br />

drug in the appropriate area of the intestinal<br />

tract at a predetermined rate to address<br />

inflammation locally and optimally. Initially, the<br />

drug will be developed for the treatment of<br />

ulcerative colitis. Manufacturing of clinicalgrade<br />

material is planned to start in <strong>2023</strong>, with<br />

the goal of filing a clinical trial application in<br />

2024.<br />

Thomas A. Tóth von Kiskér, CEO and<br />

Board Director of Tillotts, commented:<br />

“We are excited to team up with TVM Capital<br />

Life Science to advance this oral antibody<br />

in ulcerative colitis, a lifelong disease<br />

profoundly impacting the patients’ quality of<br />

life. The collaboration with TVM underpins<br />

Tillotts’ leading role in developing and<br />

condition. I look forward to advancing our<br />

antibody to clinical proof of concept.”<br />

About ulcerative colitis<br />

Ulcerative colitis (UC) is an inflammatory<br />

bowel disease (IBD) that impacts millions of<br />

people worldwide. Ulcerative colitis affects<br />

the innermost lining of the colon and the<br />

rectum, causing inflammation and ulcers in<br />

the digestive tract. In most people, symptoms<br />

usually develop over time, taking a relapsingremitting<br />

course, which means that periods of<br />

flare-ups are followed by periods of remission.<br />

This can be draining and, in some cases,<br />

lead to life-threatening complications. While<br />

there is no known cure, current treatments<br />

aim to reduce signs and symptoms of the<br />

disease and bring remission. Over the last<br />

decade, biologics have gained an important<br />

place in the treatment of ulcerative colitis,<br />

with several monoclonal antibodies available<br />

as subcutaneous or intravenous therapies<br />

approved for use in UC. Unfortunately,<br />

a substantial proportion of patients do<br />

not respond, lose response, or develop<br />

intolerance to currently marketed products,<br />

leading to a substantial unmet medical need<br />

for safer, effective, and more convenient<br />

therapeutic options.<br />

Novel antibody specifically designed<br />

for oral administration utilizes Tillotts<br />

Pharma’s sustained release approach to<br />

ensure optimal and local treatment<br />

Mage Biologics is the 10th earlystage<br />

or project focused company<br />

(PFC) investment for TVM Life Science<br />

Innovation II Fund.<br />

Montreal, Canada / Munich, Germany /<br />

Rheinfelden, Switzerland – 20 July <strong>2023</strong><br />

– Life Science Newswire – TVM Capital Life<br />

Science (“TVM”), a leading international<br />

venture capital firm focused on investments<br />

in life sciences innovation, together with<br />

specialty pharma company, Tillotts Pharma<br />

(“Tillotts”), today announced that the<br />

companies will jointly invest up to USD<br />

28 million in the newly formed U.S.-based<br />

biotechnology company, Mage Biologics Inc.<br />

(“Mage Bio”). TVM will invest with its fund TVM<br />

Life Science Innovation<br />

II SCSp (“TVM LSI II”) and will provide<br />

strategic advice to Mage Bio, with Dr. Sascha<br />

Berger, General Partner, joining the Board of<br />

Directors and Dr. Ivan Shaw, Principal, serving<br />

as a Board Observer. Mage Bio is the 10th<br />

commercializing innovative products in the<br />

gastrointestinal field.”<br />

“TVM Capital Life Science is proud to have<br />

enabled the creation of Mage Biologics.<br />

This investment is again a testament to our<br />

strong international network and builds<br />

on our successful single asset focus for<br />

innovative preclinical therapeutic agents,”<br />

said Sascha Berger, General Partner of<br />

TVM Capital Life Science and Member<br />

of the Board of Mage Biologics. “We are<br />

pleased to collaborate with the experienced<br />

management team of Johannes Spleiss and<br />

Chantal Miklosi, who will act as CEO and<br />

CFO, respectively, for Mage Biologics.”<br />

Johannes Spleiss, Head of Scientific<br />

Affairs at Tillotts and CEO of Mage<br />

Biologics, added: “We are taking a new and<br />

potentially disruptive approach to overcome<br />

the challenges with traditional ulcerative colitis<br />

treatments with this oral antibody. Developing<br />

more efficacious therapies with a greater<br />

likelihood of success and less systemic side<br />

effects is an important step in continuing to<br />

innovate for the many patients living with this<br />

About the project-focused company (PFC)<br />

For its PFC investments, TVM has a unique<br />

arrangement with Eli Lilly and Company<br />

(“Lilly”), which is a limited partner in TVM LSI<br />

II and the earlier fund TVM LSI I, under which<br />

TVM and its PFCs have the option to engage<br />

Chorus, a full-service autonomous research<br />

and development unit within Lilly, to assist the<br />

PFC by implementing a lean and focused drug<br />

development plan, resulting in high-quality<br />

data packages to help determine proof of<br />

concept.<br />

About Tillotts Pharma<br />

Tillotts Pharma AG, part of the Japanese Zeria<br />

Group, is a fast-growing specialty pharma<br />

company with close to 400 employees<br />

in Switzerland and abroad. Tillotts is<br />

dedicated to the development, acquisition<br />

and commercialization of innovative<br />

pharmaceutical products for the digestive<br />

system. Tillotts successfully markets its<br />

own products for the treatment of IBD and<br />

Clostridioides difficile infection (CDI) as well as<br />

in-licensed products in around 65 countries<br />

through its affiliates within Europe and a<br />

network of partners throughout the world.<br />

GASTROENTEROLOGY TODAY – AUTUMN <strong>2023</strong><br />

31


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