Download Ulcerative colitis-moderately and severely active

2015/16 PBR Exclusions – Funding Application for
Infliximab, Adalimumab, Golimumab and Vedolizumab for treating Moderately to
Severely Active Ulcerative Colitis (Final version 1: Last updated 16/07/2015)
Before providing patient identifiable data on this form, please confirm that the patient (or in the case of a minor or vulnerable adult with the parent/legal guardian/carer) has given appropriate explicit
consent for sensitive personal information on this form to be passed to the CCG and/or CSU for processing this funding request and validating subsequent invoices. Consent given: Yes
If there is more than one NICE-approved treatment available, a discussion between the responsible clinician and the patient has taken place about the advantages and disadvantages of the
treatments available. This has taken into consideration therapeutic need and whether or not the patient is likely to adhere to treatment. The least expensive will be chosen (taking into account
administration costs, dosage and price per dose) unless an order of preference is stated in the TAs.
Yes
Patient NHS Number:
Trust:
Patient Hospital Number:
Patient Birth Year:
Requesting Consultant:
(yyyy)
Patient Status:(* select 1 option)
NHS
Private
Overseas Consultant Contact Details:
Please indicate whether the patient meets ALL of the following criteria
1. Is the patient aged 18 years or over?
2. Patient has moderately or severely active Ulcerative Colitis that would normally be managed in an outpatient setting
and does not require hospitalisation or the consideration of urgent surgical intervention.
GP Name:
GP /Practice code:
Practice Postcode:
Please tick
Only fully completed forms will be
Yes
No accepted by CCGs/CSUs for
consideration.
If the answer to any of these
Yes
No
questions is NO, please consider if
*For acute exacerbations of acute severely active ulcerative colitis use ‘Funding application for Infliximab for acute
exacerbations of Ulcerative Colitis’ (NICE TA 163)*
there are patient specific
3. Patient had responded inadequately to conventional therapy before starting any biologic drug including corticosteroids
exceptional clinical circumstances
Yes
No
and mercaptopurine or azathioprine, or cannot tolerate, or has medical contraindications for such therapies.
demonstrated. If so, a full
Please indicate that the patient has either not responded/ individual funding request (IFR)
Which treatments have been tried in this
Start
Stop
Dose
is intolerant/ has a contraindication to or is continuing form will need to be completed.
patient before any biologic (tick which applies)
date
date
This may be obtained from the
on treatments (provide details including type of intolerance)
named contact at the relevant
5-ASA (specify:
)
CCG/CSU/Trust. Please refer to the
Corticosteroids
individual CCG IFR policy for
Azathioprine**
further details.
6-Mercaptopurine**
Other non-biologic treatment (please specify)
Contact details:
Form completed by:
Other non-biologic treatment (please specify)
Email (NHS net):
Phone:
** Azathioprine/6-Mercaptopurine should be given at maximum tolerated doses for a minimum of 3 months following dose titration.
Consider switch to 6-Mercaptopurine in case of adverse drug reactions with Azathioprine before starting biologic. In case of deranged liver function
Date of completion:
consider adding Allopurinol to reduced dose thiopurine before starting biologic.
Biologic history (where applicable)
Adalimumab
Golimumab
Infliximab
Vedolizumab
Start date
Stop date
Reason for stopping (including remissions)
Additional Information:
Participating CCGs: Barking&Dagenham; Barnet; Brent; Camden; Central London; City& Hackney; Croydon; Ealing; Enfield; Hammersmith&Fulham; Haringey; Harrow; Havering; Hillingdon; Hounslow;
Islington; Kingston; Merton; Newham; Redbridge; Richmond; Sutton; Tower Hamlets; Waltham Forest; Wandsworth; West London
This form should be returned to the named contact at the relevant CCG/CSU
Page 1 of 9
4.
5.
6.
One of the following options applies (select one option):
Patient is biologic naïve (go to 6)
CCG approved 1st line biologic treatment had to be stopped due to an adverse event before efficacy could be
assessed. (Adalimumab 8 weeks, Golimumab/Infliximab 14 weeks, Vedolizumab 10 weeks). Provide brief details on
adverse event:
(go to 6)
Patient was responding to CCG approved 1st line biologic treatment but this had to be stopped due to an adverse
event after 8 weeks (Adalimumab), 14 weeks (Golimumab/Infliximab) or 10 weeks (Vedolizumab) of initiation. Provide
details on adverse event:
(go to 5)
Patient had responded to treatment with 3 doses of Infliximab after an acute exacerbation of ulcerative colitis
(initiated under NICE TA 163) in the past and despite subsequent optimisation of conventional (non-biologic) therapy
has moderate to severe ulcerative colitis (go to 6)
Patient has responded to a CCG approved 1st line biologic treatment (for moderately to severely active ulcerative
colitis) in the past and requires retreatment for a moderate or severely active Ulcerative Colitis episode that has not
responded adequately to dose optimisation of conventional (non-biologic) therapy (go to 6)
Request is for Vedolizumab - Patient had an inadequate response or has lost response to CCG approved 1 st line
biologic. Please provide brief details:
Start date:
Stop date:
(go to 6)
Yes
No
Sequential treatment with anti-TNF inhibitors (Adalimumab, Golimumab, Infliximab) due to primary or secondary failure of a biologic is
not routinely commissioned.
There is evidence of response to biologic treatment and all of the following applies (provide details below then go to 7)
There was a decrease in full Mayo score from baseline of at least 3 points and at least 30% OR partial Mayo score
of at least 2 points and 25%
Yes
There was a decrease in the rectal bleeding sub-score from baseline of at least 1 point OR the absolute rectal
bleeding sub-score was 0 or 1
Patient was NOT yet in clinical remission (e.g. Mayo score > 2 with individual sub-scores > 1).
Prior to biologic
When stopping biologic
Measurement
Change
[see page 8 for details of Mayo score]
treatment
due to adverse event
Full Mayo score OR
points
%
Total:
Date:
Total:
Date:
Partial Mayo score* (select one)
Stool frequency
Rectal bleeding
points
Endoscopic findings (N/A for partial Mayo)
Physician global assessment
*If partial Mayo score is used, provide
mcg/g Date:
mcg/g Date:
Faecal Calprotectin level (if available)
One of these applies after failure of optimised conventional therapy and prior to starting requested course of biologic
treatment [see page 8 for details of Mayo score] (tick one and provide details):
Yes
Full Mayo score > 6. Score:
Date:
OR
Partial Mayo score > 4. Score:
Date:
AND Faecal Calprotectin >100mcg/g:
mcg/g Date:
No
No
(if available)
Stool frequency
Rectal bleeding
Endoscopic findings (N/A for partial Mayo)
Physician global assessment
Page 2 of 9
7.
Please specify which drug is requested:
Adalimumab (go to 10)
Remsima® (infliximab biosimilar)* (go to 10)
Golimumab (go to 8)
Inflectra® (infliximab biosimilar)* (go to 10)
Vedolizumab (go to 9)
Remicade® (infliximab)* (go to 10)
*Remsima® is the preferred Infliximab brand for all London Trusts.
Please provide valid reason, if not using preferred biosimilar:
Note: In London Adalimumab (standard dose) is the least expensive followed by Golimumab, Infliximab biosimilar (taking into account
cost of administration for the latter), Infliximab (Remicade®) and Vedolizumab. Vedolizumab is the most expensive biologic and should
therefore not normally be considered as first line treatment.
Sequential treatment with anti-TNF inhibitors (Adalimumab, Golimumab, Infliximab) due to primary or secondary failure of a biologic is not routinely
commissioned.
8.
For Golimumab, the manufacturer will provide the 100mg dose at the same cost as the 50mg dose (go to 10)
9.
For Vedolizumab, the manufacturer will provide the drug at the discount agreed in the patient access scheme.
10. Licensed induction and standard* maintenance dose / frequency of requested biologic drug will be used?
(*Vedolizumab 8 weekly)
Drug dose and frequency:
For Infliximab: Patient weight
kg
11. What is acquisition cost per month/dose at maintenance dose (including VAT if applicable)
Note: CCGs will not pay more than the London Procurement list price/PAS price. Commercial in confidence for
Trust/CCG/CSU
Yes
No
Yes
No
Yes
No
£
£
/ dose (Infliximab/Vedolizumab)
/ month (Adalimumab/Golimumab)
FOR CCG/CSU USE ONLY
Monitoring and Stopping Criteria
Funding is approved for a planned
course of treatment (for an induction
period followed by maintenance
treatment) until treatment failure
(including the need for surgery) or
until 12 months after the start of
treatment (whichever is shorter)
Funding is re-approved (12 monthly
intervals)
Trial withdrawal: Following the 12 months planned course, treatment should only be continued if there is clear evidence of response as
determined by clinical symptoms, biological markers and investigation, including endoscopy if necessary. According to NICE TA, a trial
withdrawal from treatment should be considered for all patients who are in stable clinical remission. (See 4.4 – A Mayo score of 2 or less
with no individual sub-score greater than 1 is considered to be remission)
If continued treatment is appropriate: If a patient is to continue with treatment beyond 12 months (rather than a trial withdrawal), the
clinician is required to write to the CCG/CSU with a clinical update providing details that the patient has had a response to treatment but
that they are not in stable clinical remission. The following should be provided at this point as per NICE TA (section 4.4)
 Decrease in full Mayo score from baseline of at least 3 points and at least 30 % or partial Mayo score of at least 2 points and
Yes
No
Yes
No
25%.

A decrease in the rectal bleeding sub-score from baseline of at least 1 point, or having an absolute rectal bleeding sub-score of 0 or 1.
If patient relapses after trial withdrawal, please complete a new application to re-start treatment.
Page 3 of 9
Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy
(including a review of NICE TA 140 and TA 262) (NICE TA 329: February 2015)
1.1 Infliximab, adalimumab and golimumab are recommended, within their marketing authorisations, as options for treating moderately to severely active ulcerative colitis in adults
whose disease has responded inadequately to conventional therapy including corticosteroids and mercaptopurine or azathioprine, or who cannot tolerate, or have medical
contraindications for, such therapies.
Golimumab is recommended only if the company provides the 100 mg dose of golimumab at the same cost as the 50 mg dose, as agreed in the patient access scheme.
1.2 The choice of treatment between infliximab, adalimumab or golimumab should be made on an individual basis after discussion between the responsible clinician and the
patient about the advantages and disadvantages of the treatments available. This should take into consideration therapeutic need and whether or not the patient is likely to
adhere to treatment. If more than 1 treatment is suitable, the least expensive should be chosen (taking into account administration costs, dosage and price per dose).
1.4 Infliximab, adalimumab or golimumab should be given as a planned course of treatment until treatment fails (including the need for surgery) or until 12 months after starting
treatment, whichever is shorter. Specialists should then discuss the risks and benefits of continued treatment with the patient, and their parent or carer if appropriate:
 They should continue treatment only if there is clear evidence of response as determined by clinical symptoms, biological markers and investigation, including endoscopy
if necessary. People who continue treatment should be reassessed at least every 12 months to determine whether ongoing treatment is still clinically appropriate.
 They should consider a trial withdrawal from treatment for all patients who are in stable clinical remission. People whose disease relapses after treatment is stopped
should have the option to start treatment again.
2.3 The modified Truelove and Witts severity index is widely used to classify the severity of ulcerative colitis. It defines mild ulcerative colitis as fewer than 4 bowel movements
daily; moderate ulcerative colitis as more than 4 daily bowel movements but the patient is not systemically ill; and severe ulcerative colitis as more than 6 bowel movements
daily and the patient is also systemically ill (as shown by tachycardia, fever, anaemia or a raised erythrocyte sedimentation rate). Severe ulcerative colitis, as defined by the
Truelove and Witts severity index, is potentially life threatening and normally requires hospitalisation and emergency care. This is aligned with the UK definition of 'acute
severe ulcerative colitis'. NICE's guideline on ulcerative colitis equates 'subacute ulcerative colitis' to moderately to severely active ulcerative colitis, which would normally be
managed in an outpatient setting and does not require hospitalisation or the consideration of urgent surgical intervention. This appraisal includes moderately to severely active
ulcerative colitis but not acute severe ulcerative colitis (that is, severe ulcerative colitis according to the Truelove and Witts severity index). Recommendations for treating
acute severe ulcerative colitis can be found in NICE's guideline on managing ulcerative colitis and NICE's technology appraisal guidance on infliximab for acute exacerbations
of ulcerative colitis.
4.2 All the RCTs except the study by Probert et al. used the Mayo score to assess the eligibility of patients. The Mayo score assesses 4 outcomes (stool frequency, rectal
bleeding, endoscopic findings and physician's global assessment) on a scale of 0–12, with the score increasing with disease severity. In all these trials patients were eligible if
they had a Mayo score of 6–12 with disease identified by endoscopic examination, which represents moderate to severe disease. Probert et al. used instead the ulcerative
colitis symptom score, but the Assessment Group considered this to be equivalent to the Mayo score. Patients had to have taken conventional therapies before. These
therapies varied across the trials but generally included corticosteroids, aminosalicylates and/or a drug that affects the immune response. Only in ULTRA2 were patients
allowed to have had a TNF‑alpha inhibitor before (40% of patients had been treated with one). Patients were excluded from the trials if they had any of the following:
ulcerative proctitis (ulcerative colitis that is limited to the rectum), a history of or a risk of having bowel surgery, diseases of the central nervous system, previous serious
infection or a deficient immune system, previous cancer, or dysplasia (signs of abnormal growth of cells).
4.4 The primary end point in all the RCTs was clinical response or remission. Of the 9 trials in adults, 8 trials assessed how well the treatment induced clinical response or
remission, and 6 trials assessed how well the treatment maintained it (5 trials assessed both). To assess clinical response or remission, all trials except the study by Probert et
al. used the Mayo score, which the Assessment Group considered to be applied consistently in the individual trials. Probert et al. used the ulcerative colitis symptom score. In
the trials that used the Mayo score, clinical response was generally defined as:
 a decrease in Mayo score from baseline of at least 3 points and at least 30%, and
 a decrease in the rectal bleeding sub‑score from baseline of at least 1 point, or having an absolute rectal bleeding sub‑score of 0 or 1.
Similarly, the definition of remission was broadly the same across the RCTs: Mayo score of 2 or less, with no individual sub‑score greater than 1.
Page 4 of 9
Vedolizumab for treating moderately to severely active ulcerative colitis (NICE TA 342: June 2015)
1.1 Vedolizumab is recommended, within its marketing authorisation, as an option for treating moderately to severely active ulcerative colitis in adults only if the company provides
vedolizumab with the discount agreed in the patient access scheme.
1.2 Vedolizumab should be given until it stops working or surgery is needed. At 12 months after the start of treatment, people should be reassessed to see whether treatment
should continue. Treatment should only continue if there is clear evidence of ongoing clinical benefit. For people in complete remission at 12 months, consider stopping
vedolizumab, resuming treatment if there is a relapse. People who continue vedolizumab should be reassessed at least every 12 months to see whether continued treatment is
justified.
2.1 … The marketing authorisation states that vedolizumab is indicated 'for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an
inadequate response with, or lost response to, or were intolerant to either conventional therapy or a tumour necrosis factor-alpha antagonist'. The recommended dosage of
vedolizumab is 300 mg given by intravenous infusion at 0, 2 and 6 weeks and then every 8 weeks thereafter. Continued therapy for people with ulcerative colitis should be
carefully reconsidered if no evidence of therapeutic benefit is observed by week 10.
3.1 … Clinical response was measured using the Mayo score, which included assessment of stool frequency, rectal bleeding, an endoscopic assessment and a global
assessment by a clinician. Clinical response was defined as a reduction in the Mayo score of at least 3 points and a decrease of at least 30% from baseline, with an
accompanying decrease in the rectal bleeding subscore of at least 1 point or an overall rectal bleeding subscore of 1 point or less. Secondary outcomes included clinical remission
(Mayo score of up to 2 points and no individual subscore greater than 1 point) and mucosal healing (defined as an endoscopic subscore of 1 point or less).
3.2 GEMINI I included people who had moderate to severely active ulcerative colitis at baseline (Mayo score of 6 to 12).
3.6 … Clinical response was assessed by the partial Mayo score (that is, the Mayo score without the sigmoidoscopy subscore). Response was defined as a reduction of at least 2
points and a decrease of at least 25% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of
up to 1 point.
Costing statement: Ulcerative colitis – Implementing the NICE guidance on infliximab, adalimumab and golimumab for treating moderately to severely
active ulcerative colitis after the failure of conventional therapy (TA329)
Maintenance doses of adalimumab (40 mg) may in some cases be used each week, as opposed to every 2 weeks (the standard regimen). Based on a response to the consultation it has been
assumed that 15.9% of people receiving adalimumab are treated every week. Costs vary depending the dose prescribed, and.the above costs for adalimumab have been weighted to reflect this.
c
Costing statement: Ulcerative colitis – Implementing the NICE guidance on vedolizumab for treating moderately to severely active ulcerative colitis
after the failure of conventional therapy (TA342)
a Induction
doses at 0,2 and 6 weeks. Maintenance doses every 8 weeks thereafter.
NICE enq ref EH56265 RE: NICE technology appraisal guidance [TA329]
– email correspondence 06th May 2015
I can advise you that the guidance does not cover the sequential use of treatments as this was outside the scope of the appraisal. This means that it is the responsibility of local commissioners to
make their own decisions regarding funding of TNF-alpha inhibitors after previous failure or adverse events. We have reviewed the SPCs and they do not make any mention on the use of the
drugs in people who have previously received a different TNF-alpha inhibitor, although they are not contraindicated in these people.
Page 5 of 9
Summary of Product Characteristics- Adalimumab (Humira®)
(ref: www.medicines.org.uk. Accessed 11/05/2015; SPC last updated 09/04/2015)
4.2 Posology and method of administration:
The recommended Humira induction dose regimen for adult patients with moderate to severe ulcerative colitis is 160 mg at Week 0 (dose can be administered as four injections in one day or as two
injections per day for two consecutive days) and 80 mg at Week 2. After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection.
During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines.
Some patients who experience decrease in their response may benefit from an increase in dosing frequency to 40 mg Humira every week.
Available data suggest that clinical response is usually achieved within 2-8 weeks of treatment. Humira therapy should not be continued in patients failing to respond within this time period.
Summary of Product Characteristics- Golimumab (Simponi®)
(ref: www.medicines.org.uk. Accessed 11/05/2015; SPC last updated 14/05/2015)
4.2 Posology and method of administration:
Patients with body weight less than 80 kg - Simponi given as an initial dose of 200 mg, followed by 100 mg at week 2, then 50 mg every 4 weeks, thereafter (see section 5.1).
Patients with body weight greater than or equal to 80 kg - Simponi given as an initial dose of 200 mg, followed by 100 mg at week 2, then 100 mg every 4 weeks, thereafter (see section 5.1).
During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines.
Available data suggest that clinical response is usually achieved within 12-14 weeks of treatment (after 4 doses). Continued therapy should be reconsidered in patients who show no evidence of
therapeutic benefit within this time period.
Summary of Product Characteristics- Infliximab (Remsima®/Inflectra®/Remicade®)
(ref: www.medicines.org.uk. Accessed 11/05/2015; SPC last updated 25/02/2015 – Remsima/Inflectra; 29/08/2015 Remicade)
4.2 Posology and method of administration:
5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.
Available data suggest that the clinical response is usually achieved within 14 weeks of treatment, i.e. three doses. Continued therapy should be carefully reconsidered in patients who show no
evidence of therapeutic benefit within this time period.
Summary of Product Characteristics- Vedolizumab (Entyvio®) (ref: www.medicines.org.uk. Accessed 12/06/2015; SPC last updated 17/04/2014)
4.2 Posology and method of administration:
The recommended dose regimen of Entyvio is 300 mg administered by intravenous infusion at zero, two and six weeks and then every eight weeks thereafter.
Continued therapy for patients with ulcerative colitis should be carefully reconsidered if no evidence of therapeutic benefit is observed by Week 10.
Summary of Product Characteristics- Azathioprine (Sandoz) (ref: www.medicines.org.uk. Accessed 11/05/2015; SPC last updated 29/04/2014)
4.1 Therapeutic indications:
Therapeutic effect may be evident only after weeks or months and can include a steroid-sparing effect, thereby reducing the toxicity associated with high dosage and prolonged usage of
corticosteroids.
4.2 Posology and method of administration
When therapeutic response is evident, consideration should be given to reducing the maintenance dosage to the lowest level compatible with the maintenance of that response. If no improvement
occurs in the patient's condition within 3 months, consideration should be given to withdrawing the medicinal product.
Guidelines for the management of inflammatory bowel disease in adults (2011)
(ref: Mowat C, Cole A, Windsor A, et al. Gut (2011). Doi:10.1136/gut.2010.224154. www.rheumatology.org.uk, Accessed 21/01/2015)
Dosing Tailoring or optimisation of thiopurine therapy can occur prior to or during treatment. The appropriate maintenance dose of AZA is 2e2.5 mg/kg/day and of MP is 0.75e1.5 mg/kg/day in both
ulcerative colitis and Crohn’s disease. The ‘maximum’ dose will differ between individuals and effectively means that level at which leucopenia develops. There is some evidence that mesalazine has
synergistic effects on thiopurine therapy but the mechanism of this effect is unclear.
5.0 MANAGEMENT OF ULCERATIVE COLITIS
http://www.bsg.org.uk/forum (accessed Oct 2010)
Therapeutic decisions depend on disease activity and extent. Disease activity is best evaluated objectively using a clinical activity index (the Truelove and Witts263 or the Mayo Clinic disease activity
index.264 Patients with severe disease require hospital admission, while those with mild/moderate disease can generally be managed as outpatients.
Page 6 of 9
Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn’s disease (2014)
(ref: Ruemmele, FM, Veres G, Kolho KL, et al. Journal of Crohn’s and Colitis (2014), 81179-1207)
3.1 Thiopurines - Statement 9
7. A switch between azathioprine (AZA) and 6-mercaptopurine (6-MP) can be considered in patients who develop flu-like or acute gastrointestinal symptoms.
9. Determination of thiopurine metabolites (6TGN and 6MMP) should be considered in patients with elevated Alanine transaminase (ALAT), cytopenia, or in suboptimal response and to monitor
compliance (Table 2).
10. If allopurinol is added, the thiopurine dose should be reduced to 25–33% of the original dose, and metabolites re-evaluated. The standard adult allopurinol dose is 100 mg/d, for children
allopurinol doses should be reduced (to 50–75 mg according to body weight).
Table 2 Interpretation of thiopurine metabolite profiles in case of suspected dose-dependent adverse events or refractoriness.
6-TGN
(pmol/8.108 RBC)
Low (< 230)
6-MMP
(pmol/8.108 RBC)
Low–normal
(< 5700)
Low (< 230)
High (≥5700)
Therapeutic (230–
450)
Normal or high
High (> 450)
Normal
High
High
Dose-dependent
adverse event
Hepatotoxicity and
others
Hepatotoxicity and
others
Interpretation
Recommendation
Under-dosing or low
compliance
Increase compliance or thiopurine dose as appropriate
TPMT hyper-metabolizers
Consider allopurinol co-treatment and dose reduction to 25–33% of standard
dose; or change medication
Therapy failure
If clinically resistant, change drug category
Myelosuppression
Low TPMT activity
(heterozygote or homozygote)
Myelosuppression
and hepatotoxicity
Overdosing
Switch type of immunomodulation if homozygote (or absent TPMT activity) or
reduce dose to half if heterozygote (or moderately low TPMT activity)
Reduce dose and if clinically resistant-change drug category
The cut-off values given in this table are based on the method according to Lennard; higher cut-off values (therapeutic range of 6TGN from 600 to 1200 pmol/8.108 RBC) are necessary when analyses are
based on the method of Dervieux and Boulieu.
A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an
observational study, systematic review and meta-analysis.
(ref: Kennedy NA, Rhatigan E, Arnott IDR et al. Aliment Pharmacol Ther 2013;38:1255-1266)
Abstract
BACKGROUND: Thiopurines maintain remission and modify disease course in inflammatory bowel disease. Use is limited by intolerance and subsequent drug withdrawal in approximately 17% of
patients treated with azathioprine. Previous case series have addressed the success rates of re-treatment with mercaptopurine in these individuals.
AIMS: To determine the rate of tolerance when trialling mercaptopurine in azathioprine-intolerant patients and the factors predictive of success, and to perform a systematic review and meta-analysis
of these data with other published data sets.
METHODS: A retrospective observational study of 149 patients with IBD (82 with Crohn's disease and 67 with ulcerative colitis) previously intolerant of azathioprine subsequently treated with
mercaptopurine was performed. A meta-analysis was undertaken of all published studies of mercaptopurine use in azathioprine-intolerant patients (455 patients in 11 included studies).
RESULTS: Mercaptopurine was tolerated by 58% of azathioprine-intolerant patients in the Edinburgh cohort. In the meta-analysis, 68% tolerated mercaptopurine. A higher proportion of those in the
meta-analysis with GI toxicity (62%) or hepatotoxicity (81%) were able to tolerate mercaptopurine than those with flu-like illness (36%). Among those patients who ceased mercaptopurine for further
adverse effects, 59% experienced the same adverse effect as they had with azathioprine.
CONCLUSIONS: This meta-analysis shows that switching to mercaptopurine is a safe therapeutic strategy for over two-thirds of azathioprine-intolerant patients and may help optimise
immunomodulatory therapy in inflammatory bowel disease. A trial of mercaptopurine should be attempted in IBD patients (except those with acute pancreatitis or bone marrow aplasia) before
considering thiopurine intolerance.
Page 7 of 9
Ulcerative colitis Management in adults, children and young people (NICE CG 166, June 2013)
Table 1 Truelove and Witts' severity index
Mild
Moderate
Bowel movements (no. per day)
Fewer than 4
4–6
Blood in stools
Pyrexia (temperature greater than 37.8°C) *
Pulse rate greater than 90 bpm *
Anaemia *
Erythrocyte sedimentation rate (mm/hour) *
No more than small amounts of blood
No
No
No
30 or below
Between mild and severe
No
No
No
30 or below
Severe
6 or more plus at least one of the features of systemic upset
(marked with * below)
Visible blood
Yes
Yes
Yes
Above 30
© Copyright British Medical Journal, 29 October 1955. Reproduced with permission.
Mayo Scoring System for Assessment of Ulcerative Colitis Activity
(ref: Rutgeerts P, Sandborn W, Feagan B, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. NEJM (2005);353(23):2462-76.)
Table 1. Mayo Scoring System for Assessment of Ulcerative Colitis Activity.*
Stool frequency
0 = Normal no. of stools for this patient
Subscore 0 to 3
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than normal
Rectal bleeding
Subscore 0 to 3
0 = No blood seen
1 = Streaks of blood with stool less than half the time
2 = Obvious blood with stool most of the time
3 = Blood alone passes
Findings on endoscopy
0 = Normal or inactive disease
Subscore 0 to 3
1 = Mild disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate disease (marked erythema, lack of vascular pattern, friability,erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
Physician’s global assessment
0 = Normal
Subscore 0 to 3
1 = Mild disease
2 = Moderate disease
3 = Severe disease
* The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease. Data are from Schroeder et al.
Page 8 of 9
Can Endoscopy Be Avoided in the Assessment of Ulcerative Colitis in Clinical Trials? Guidelines for the management of inflammatory
bowel disease in adults (2011)
(ref: Dhanda A, Creed T, Greenwood R, et al (InflammBowel Dis 2012;18:2056-2062)
Background: There is no gold standard index in the measurement of ulcerative colitis (UC) disease activity in clinical trials. Mucosal healing has been described as an important
clinical endpoint requiring endoscopic assessment, which is unpleasant for the patient and may hamper recruitment to trials. The aim of this study was to determine whether
endoscopy is necessary in the assessment of UC disease activity and whether a noninvasive disease activity index (partial Mayo score) could be used to predict the Mayo score.
Methods: In all, 149 subjects with moderate to severe UC enrolled in a clinical trial were assessed using total and partial Mayo scores. Histologic assessment of biopsies was
performed. A regression model was constructed to predict total Mayo score from the partial Mayo score and histology score from the Mayo score. A Bland–Altman test of
agreement was performed.
Results: The partial Mayo score correlated closely with the total Mayo score at week 4 (rho ¼ 0.97) and week 8 (rho ¼ 0.98). The model to predict total from partial Mayo score
showed excellent correlation (rho ¼ 0.97) and good agreement with the total Mayo score at week 4 and the week 8 validation set (rho ¼ 0.97) and accurately classified disease
severity (kappa ¼ 0.82). The model to predict histology score from the Mayo score correlated only moderately with the actual histology score at week 4 (rho ¼ 0.59) and week 8
(rho ¼ 0.36).
Conclusions: The Mayo score can be accurately predicted from the partial Mayo score. A noninvasive index can replace the Mayo score in future clinical trials.
Use of the Non-Invasive Components of the Mayo Score to Assess Clinical Response in Ulcerative Colitis (2008)
(ref: Lewis J, Chuai S, Nessel L, et al (Inflamm Bowel Dis 2008;14(12):1660-1666)
Background—The Mayo score and a non-invasive 9-point partial Mayo score are used as outcome measures for clinical trials assessing therapy for ulcerative colitis. There are
limited data assessing what defines a clinically relevant change in these indices. We sought to assess what constitutes a clinically meaningful change in these indices using data
from a recently completed placebo-controlled clinical trial.
Methods—105 patients were enrolled in a 12 week randomized, placebo-controlled trial assessing rosiglitazone for treatment of mild to moderate ulcerative colitis. We compared
the change in the Mayo score, the partial Mayo score, and a 6 point score composed just of the stool frequency and bleeding components of the Mayo score to the patient’s
perception of disease activity at week 0 and week 12. Optimal cut points were calculated as the maximal product of sensitivity and specificity.
Results—Each index was strongly correlated with the patient’s rating of disease activity at week 12 (Spearman correlations from 0.61 to 0.71, p<0.0001 for all correlations). The
maximal product of sensitivity and specificity to identify patient reported improvement of disease activity was achieved using cut points for change of 2.5 for the Mayo score
(sensitivity 88%, specificity 80%), 2.5 for the partial Mayo score (sensitivity 88%, specificity 87%), and 1.5 for the 6 point score (sensitivity 88%, specificity 80%).
Conclusion—The partial Mayo score and the 6 point score composed solely of the stool frequency and bleeding components performed as well as the full Mayo score to identify
patient perceived clinical response.
Faecal calprotectin diagnostic tests for inflammatory diseases of the bowel. NICE DG11: October 2013)
1.1 Faecal calprotectin testing is recommended as an option to support clinicians with the differential diagnosis of inflammatory bowel disease (IBD) or irritable bowel syndrome
(IBS) in adults with recent onset lower gastrointestinal symptoms for whom specialist assessment is being considered, if:
 cancer is not suspected, having considered the risk factors (for example, age) described in Referral guidelines for suspected cancer (NICE CG27),
and
 appropriate quality assurance process and locally agreed care pathways are in place for the testing.
4.4 … the most common cut-off recommended by manufacturers is 50 micrograms/g. It should be noted that, in some cases, people with IBS can have raised levels of faecal
calprotectin above the selected cut-off value and the opposite is true for people with IBD (faecal calprotectin levels can be below the selected cut-off).
The role and utility of faecal markers in inflammatory bowel disease
(ref: Lehmann F, Burri E, Beglinger C. Ther Adv Gastroenterol 2015, Vol. 8(1) 23–)36
For clinical use, a calprotectin level of less than 50 μg/g is negative, 50–100 weakly positive, and over 100 positive.
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