Argument in favour of continuing 5-ASA:

1. 5-ASA has been shown to inhibit TPMT. This will increase 6-thioguanine levels (active metabolite of thiopurines) and hence may increase the therapeutic efficacy of azathioprine/6-MP (not meaningful clinically)
2. 5-ASA are safe
3. 5-ASA have possible chemopreventive properties

Arguments against continuing 5-ASA:

1. No evidence of additive clinical benefit (ref: Andrews et al. Aliment Pharmacol Ther. 2009;29(5):459-69)
2. Increased risk of leukopenia (due to TPMT inhibition)
3. More pills may affect adherence
4. Chemoprevention is of uncertain benefit if patient has already failed primary therapy and if increased inflammation. Further continued 5-ASA treatment does not obviate the need for surveillance colonoscopies, hence it may be argued that continuing additional pills per day is not warranted.

So, what do you do? A practical approach:

1. If failing 5-ASA, withdraw therapy to confirm that the patient is not intolerant of 5-ASA
2. If you wish to continue 5-ASA for potential chemoprevention, simplify the regimen (evidence suggest 1.2g/day)

2.    Discuss the role of thiopurine metabolites in a non responding patient?

Monitoring thiopurine metabolites is important because:

• Standard dosing only 30% effective
• Safe dose escalation to maximise efficacy
• Identify non compliance
• Minimise toxicity
• Identify preferential 6-MMP metabolism
• Explain non response
• Improves patient outcomes

The best probability of response to thiopurines was with levels of 6-TG to be greater than 235 pmol/8X108 RBC. However, a certain percentage (41%) of patient’s do achieve a therapeutic response with levels <235.

Checking thiopurine metabolites (6-TG and 6-MMP) in non responders will thus help us to assess our therapeutic options better. So,

1. Low (<235) or undetectable levels of 6-TG and 6-MMP suggest under dosing or non compliance
2. Low (<235) 6-TG and high (>5700) 6-MMP levels suggest 6-MMP shunter. You can use increased dose of thiopurines or consider adding Allopurinol (see below)
3. Therapeutic (>235-<400) or high 6-TG and high or normal 6-MMP suggests non responder to thiopurines. Will need alternative treatments

3.    Discuss the use of Allopurinol in thiopurine non responders?

Allopurinol treatment may be considered in thiopurine non responders due to preferential 6 methyl mercaptopurine (MMP) metabolism. Allopurinol interacts with thiopurine metabolism and can result in dramatic shifts in the metabolism towards 6-TG and away from 6-MMP. This is quite a potent effect and so prescribing must be done very carefully due to risks of marrow suppression and other adverse events. So:

1. Drop Azathioprine to 50 mg or 6-MP to 25mgs a day or approximately to 25% of the prior dose
2. Start Allopurinol at 100 mgs a day
3. Weekly blood counts for 4 weeks , then monthly
4. Checking thiopurine metabolites at 4-8 weeks is informative
5. Adjust dose as necessary for thiopurine but in small increments
6. NOTIFY PHARMACIST

NB: 6-MMP is also implicated in the pathogenesis of thiopurine induced hepatotoxicity. Hence, Allopurinol can also be used in clinical condition of thiopurine induced hepatotoxicity to induce preferential metabolism towards 6-TG (instead of 6-MMP)

4.    Questions about concomitant therapy with biologics

What is the rationale for combining biologics with immunomodulators?

1. Higher drug levels of biologics
2. Increased efficacy
3. Preventing immunogenicity (leading to decreased infusion reactions and reduced loss of efficacy)
4. Improving drug durability
5. We don’t understand the pathogenesis of IBD, so biologics and immunomodulators may be acting on different therapeutic targets

Discuss the evidence for combination treatment (biologics plus immunomodulators)?

1. Patients who are immunomodulators naive, combination treatment is superior to monotherapy for clinical and deep (mucosal healing) remission. SONIC trial (Colombel JF et al. N Engl J Med. 362 (15): p1383-95) showed that combination treatment achieved statistically more mucosal healing and less infusion reactions ( SONIC trial: Primary end point was week 26 steroid free remission: 44.4% with IFX alone and 56.8% with IFX plus Azathioprine i.e. 11% gain)

How do you start combination therapy? Both the biologic and immunomodulators can be started at the same time, but if on steroids, they can be staggered i.e. start biologics and then at a later date start immunomodulators.

When can you withdraw the combination therapy? Which one should it be?
There are no trials to answer this question

2. Patients failing immunomodulators treatment before biologic therapy may not benefit from combination approach. Immunomodulators in these patients can be safely withdrawn after six months without loss of response to the biologic for at least two years (ref: Van Assche G et al. Gastroenterology 2008. 134 (7): 1861-8)

What dose is needed just for preventing immunogenicity?

There are no answers from trials. However, it appears that low dose may be effective for this purpose (7.5 mg weekly of oral methotrexate or 50 mg of Azathioprine)

If you need further help to decide on single or combination therapy, please visit http://www.bridgeibd.com/. You can put in your patient characteristics and check the recommendation based on RAND appropriateness method.

5.    How would you deal with loss of response to anti-TNF?

1. Primary non responder: anti-TNF loading dose ( 2 doses at 0 and 2 weeks) with no response: try a different mechanism (like methotrexate, natalizumab or surgery) and not a different anti- TNF
2. Primary responder now relapsing (i.e. secondary failure):

It is critical to distinguish between

1. a patient who has been responding and is stable on therapy but is now suffering from an acute or subacute relapse from
2. a patient who has demonstrated progressive attenuation of response.

In situation I, the patient who is relapsing due to some external factors (infection, antibiotics exposure, possibly stress) may be treated for their acute relapse and return to their stable maintenance dosing of their anti-TNF therapy.

In situation II, the patient may be suffering from some pharmacodynamic alteration of therapy, metabolism and clearance. This will need either a pharmacodynamic adjustment (dose increase or interval decrease or both) or a different strategy altogether.

Options in secondary failure:

1. Increased dose
2. Decreased duration
3. Switch to a different anti-TNF: Evidence only exists in one direction (infliximab first), assumption is the opposite is true
4. Different mechanism: methotrexate, natalizumab or surgery

How do you choose the most appropriate option?

Measuring antibodies to infliximab and infliximab levels help. Afif et al (Afif W et al. Am J Gastroenterol 2010;105(5): 1133-9) showed that patients with measurable antibodies to infliximab were much less likely to respond to dose adjustments to infliximab than they were to a different anti-TNF therapy. Patients with low trough levels of infliximab (less than 12 mcg/nl was used) responded better to an increased dosing strategy with infliximab than switching to another anti-TNF therapy.

In the UK this issue is at present academic because there is no available commercial resource for measuring either trough levels or antibody levels. Such a resource would be valuable.

The immunomodulators commonly used in IBD and associated with an increased risk of infections include corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, anti-TNF agents and other biologics. For corticosteroids, a total daily dose equivalent to ?20 mg of prednisolone for ?2 weeks is associated with an increased risk of infections.

Viral, bacterial, parasitic and fungal infections have all been associated with the use of immuno modulator therapy in IBD. Despite different mechanisms of action, any of those drugs can lead to any type of infection. No strict correlation between a specific immuno-modulator drug and a certain type of infection has been observed. Toruner and colleagues found that corticosteroid use was more commonly associated with fungal (Candida spp.) infections, azathioprine with viral infections and anti-TNF therapy with fungal or mycobacterial infections. There was, however, considerable overlap. Furthermore, these drugs are commonly prescribed together, so the infectious event might be the consequence of cumulative immunosuppressive activity.

The following risk factors are found to be associated with increased risk of infections in rheumatoid arthritis patients. These factors are likely to be associated with increased risk in IBD patients too. The risk factors are:

• Increased age (>50)
• Chronic lung disease
• Alcoholism
• Organic brain disease
• Diabetes mellitus

Pragmatic caution is advisable when considering immuno-modulator therapy in patients with these co-morbid conditions.

Tuberculosis (TB)

Experience suggests that TB complicating treatment for IBD with corticosteroids or immunomodulators is extremely rare, although the increased risk in populations at high risk (elderly white males, alcohol abuse, patients from sub continental Asia, or Africa) should still be considered.

If TB is diagnosed, anti TB-therapy must be started, – however it appears that 5-ASA, azathioprine, methotrexate or steroids do not need to be discontinued, provided that multi drug resistant TB has been excluded.

Hepatitis C

• No Consensus could be reached for HCV screening prior to starting immunomodulators.
• Immuno-modulators can be used in IBD patients regardless of concomitant HCV infection (azathioprine has been shown to have anti HCV activity in vitro)
• As for methotrexate, a small series of hepatitis C patients with arthropathy showed no detrimental effect from treatment with methotrexate
• It is reasonable to assume (based on liver transplant data) that corticosteroids used in the treatment of IBD, have no detrimental effect on the course of HCV.
• Case series suggest that anti-TNF therapy has no adverse effect or might even improve HCV infection.
• Acute HCV infection should be treated according to standard practice without stopping immunomodulators.
• Antiviral treatment for HCV infection in conjunction with Crohn’s disease is generally not recommended, since interferon therapy may worsen disease, although this remains controversial.  This is in contrast to ulcerative colitis where interferon therapy does not appear to have an adverse affect.

Hepatitis B

• All IBD patients should be tested for HBV (HBsAg, anti-HBs, anti-HBcAb) to rule out HBV infection

• HBV vaccination is recommended in all HBV seronegative patients with IBD.

• Efficacy of hepatitis B vaccination is influenced by the number of immunomodulators given. Higher doses of the immunising antigen may be necessary to achieve success. Serological response should be measured after the completion of vaccination.

• Before and during immuno-modulator treatment, HBsAg+ carriers should receive pre-emptive therapy with anti-viral agents (nucleoside/nucleotide analogues) regardless of the degree of viremia in order to avoid hepatitis B flare.  The treatment is best started best started 2 weeks prior to the introduction of steroids, azathioprine, or anti-TNF? therapy and continued for 6 months after their withdrawal. In line with recommendations from AASLD, patients with high baseline HBV DNA levels (>2000 IU/mL), should continue antiviral treatment until endpoints applicable to immunocompetent patients are reached, according to specific guidelines for HBV treatment.  Interferon-alpha (IFN?) is best avoided for two reasons: first, IFN? may exacerbate Crohn’s disease (not UC) and second, IFN? may cause additional bone marrow suppression.

• There is no established treatment for acute HBV infection. Immunosuppressive therapy should be delayed until resolution of acute infection

HIV

• Testing for HIV should be considered for patients with IBD prior to starting immuno-modulator therapy, based on anecdotal reports of increased risk and severity of HIV related infections in patients receiving immunomodulators therapy. Re-testing is indicated for patients at high-risk.

• Immunomodulators are not necessarily contraindicated in HIV-positive patients.

• The susceptibility to infection of IBD patients suffering from HIV greatly depends on the success of HAART. When the CD4+ count is >350/?l the risk may be little different to those without HIV.

• It is reasonable to use corticosteroids for the therapy of IBD patients with HIV infection receiving HAART who have achieved immune reconstitution and undetectable viral loads, but no data are available.

• No data on the use of azathioprine in patients with IBD and active or successfully treated HIV infection are available, so as with steroids, carefully monitored treatment is appropriate if necessitated by the clinical pattern of IBD.

• Anti-TNF therapy may be given to IBD patients with co-existing HIV infection and might not have the detrimental effects on HIV infection that theory might suggest. The patient will obviously need to be carefully accessed with regards to Cd4 count, IBD activity and stage of HIV infection.

CMV

• Screening for a latent or subclinical CMV infection is not necessary before starting immuno-modulator therapy. Latent or subclinical CMV infection is no contraindication for an immunomodulators therapy.
• CMV colitis should be excluded, preferably by tissue PCR or immunohistochemistry, in immunomodulatory refractory cases of IBD before increasing immunomodulators therapy.
• In case of severe colitis with CMV detected in the mucosa during immunomodulators therapy, antiviral therapy should be initiated and discontinuation of immunomodulators considered until colitis symptoms improve.
• In case of systemic CMV infection immunomodulators therapy must be discontinued.
• Subclinical reactivation of CMV during immuno-modulator or biological therapy is common, but nearly always self-limited even if therapy is continued.  This reactivation is usually asymptomatic, or characterised by a mild, self-limited course. Serious tissue damage is very rare. It is appropriate to draw a distinction between CMV infection (detectable by serology or viral DNA), and CMV disease (such as colitis, causing end-organ damage).

VZ virus

• If the medical history of chickenpox, shingles and VZV vaccination is negative, immunisation with VZV vaccine should be performed at least 3 weeks before onset of immunomodulators therapy, and preferably at diagnosis of IBD.
• Reactivation of VZV is mainly found in patients aged >50 years or immunocompromised patients. It typically manifests as a painful, unilateral, vesicular rash distributed in one or more dermatomes. Immunosuppression increases the risk of dissemination and complications such as pneumonia, hepatitis, encephalitis, or haemorrhagic disorders (thrombocytopenia or disseminated intravascular coagulopathy).
• Unimmunised, immunocompetent adults with IBD should best receive active immunisation with a 2-dose series of live varicella vaccine at least 3 weeks before immunomodulators are started.
• Passive immunisation with a high-titre preparation of VZV IgG antibodies (VZIG) is appropriate for unimmunised, seronegative, high-risk patients with IBD (immunosuppression, pregnancy) who have had close exposure to a person with chicken pox or herpes zoster. VZIG should be given within 96 h of exposure in a recommended dose (125 units, or 1 vial/10 kg of body weight to a maximum 625 units). After administration of VZIG, patients should be observed for 28 days. In the event of clinical symptoms of VZV infection, immediate antiviral therapy should be initiated although specialist advice is best taken.

Human papilloma virus (HPV)

• Regular gynaecologic screening for cervical cancer is strongly recommended for women with IBD, especially if treated with immunomodulators. This is because of the concerns that HPV-associated tumours may be more common after years of immunomodulators therapy.

• Cervical smear testing in immunocompromised women is recommended as for the general population. A practical point is to ask female patients on immunomodulators whether they have had a cervical smear. HPV screening is not recommended for men in the general population, because there is currently no evidence that screening or treatment reduces the risk of progression to (anal) cancer in this group.

• The women with IBD and especially those on immunomodulators may be considered candidates for HPV vaccine regardless of their sexual history. Nevertheless, infection with HPV is no contraindication to immunosuppression.

Influenza

• Patients on immunomodulator therapy are considered to carry an enhanced risk for the development of influenza infections. Thus, IBD patients on immunomodulators are considered to be at risk and best receive annual trivalent inactivated influenza vaccine (TIV) vaccination. The live attenuated vaccine is not recommended.
• Seroconversion after influenza vaccine is not reduced by corticosteroids, methotrexate or anti-TNF therapy, nor by dual therapy with these agents, so monitoring the serological response is not warranted. Thiopurines or ciclosporin reduce influenza vaccine seroconversion rates.
• Antiviral treatment in patients diagnosed early with influenza during an epidemic should be considered. Prophylaxis should follow national guidelines.

Parasitic and Fungal Infections

The risk of parasitic or fungal infection in inflammatory bowel disease has not been quantified. Systemic infections are exceptional, but mortality appears to be high

There are, however, no vaccines for fungal or parasitic infections, so preventive measures depend on making immunocompromised individuals aware of the risks when travelling to endemic areas. General advice includes avoiding farms, pigeon lofts, or an extended duration of stay.

P. jiroveci (P. carinii)

• P. jiroveci (P. carinii) is now classified as an atypical fungus. For those patients on triple immunomodulators with one of these being ciclosporin or anti-TNF therapy, standard prophylaxis with co-trimoxazole is recommended if tolerated. For those on double immunomodulators, with one of these being ciclosporin or anti-TNF therapy, a Consensus could not be reached on the use of prophylactic co-trimoxazole

• There are multiple regimen for primary chemoprophylaxis: Trimethoprim–sulphamethoxazole (TMP-SMZ) is the prophylactic agent of choice with one one-strength tablet daily (80–400 mg) or half-dose daily of a double strength tablet (160–800 mg) or a double-strength tablet 3 times per week.

In the event of parasitic or fungal infection other than oral or vaginal candidiasis, immuno-modulator therapy should be stopped if possible and standard therapy for the infection implemented. Common sense dictates that if an opportunistic infection arises as a consequence or in association with immunosuppression, then it is unwise to reintroduce such therapy in that patient unless all other options are considered. None of the case reports, describe reintroduction of therapy after effective treatment of systemic parasitic or fungal infection. If a decision is made to re-introduce immuno-modulator once the infection has responded to treatment, because there are no other options for controlling the IBD, then consideration should be given to secondary prophylaxis and specialist advice taken. This takes into account the treatment options available for the IBD, the general condition and wishes of the patient.

Strep pneumoniae

• Patients with IBD on immunomodulators are considered to be at risk patients for pneumococcal infections. The most frequent and severe manifestations of pneumococcal infection are pneumococcal pneumonia and pneumococcal meningitis (with or without pneumococcal bacteremia). In cohort studies bacterial pneumonia is one of the most prevalent infections in IBD patients on immunomodulators. Thus, treatment of pneumonia/meningitis in patients on immunomodulators must always cover S.Pneumoniae (i.e. penicillin)

• Preventive strategy consists of a pneumococcal vaccination.  The 23-valent pneumococcal vaccine should ideally be administered before the start of immuno modulator therapy, since immunomodulators may reduce the antibody response to the vaccine.  Therefore, the vaccine is best administered at the time of IBD diagnosis, or at least two weeks before the start of immunomodulators. Repeat vaccination is recommended after three to five years if the patient remains on immunomodulator therapy

• Immuno-modulator therapy should be temporarily withheld until the resolution of active infection.

L. Pneumophila

• Patients with IBD on immunomodulator therapy with pneumonia should be tested for L. Pneumophila The most common route of transmission is airborne and reservoirs include aquatic systems such as cooling towers, evaporative condensers, humidifiers and decorative fountains.

• Clinically and radiologically Legionella pneumonia cannot be distinguished from pneumococcal pneumonia. The key to diagnosis is appropriate microbiological culture, in association with real-time PCR if available. Serological testing and antigen detection in the urine are also available.

• Treatment for L. pneumophila consists of macrolide or fluoroquinolone antibiotics. Empirical treatment of severe community-acquired pneumonia should always cover L.pneumophila especially in the immunocompromised.

Salmonella

• Patients receiving immunomodulators are at risk of more severe infections with Salmonella enteritidis and S. Typhimurium

• Prevention consists of food hygiene: advise immunocompromised patients to avoid the consumption of raw eggs (fresh mayonnaise), unpasteurised milk and undercooked or raw meat (including carpaccio).

• Immunomodulator therapy is best temporarily withheld until resolution of the active infection, although recurrent infection and asymptomatic carriage can occur. Confirmation of clearance through stool culture in immunocompromised patients seems advisable.

Listeria

• Patients receiving immunomodulators are at risk of systemic and central neurological infections with L. monocytogenes . The incidence appears higher in patients treated with anti-TNF therapy compared to other immunomodulators

• Prevention includes avoidance of unpasteurized milk or cheese, uncooked meat and raw vegetables,especially during pregnancy. Patients on anti-TNF therapy who present with meningitis or other neurological symptoms demand full attention and should be thoroughly investigated as soon as such symptoms develop

• Anti-TNF therapy should be discontinued during infection. No Consensus was reached on whether anti-TNF therapy should not be re started.

C. Difficile

IBD is an independent risk factor for infection with C. difficile. In IBD C. difficile is mostly community-acquired. Patients with colitis are particularly susceptible. Screening for C. difficile is recommended at every flare in patients with colonic disease. In CDAD it remains to be established whether concomitant therapy with immunomodulators should be withheld.

Pre-travel consultation

Patients with IBD should have a pre-travel consultation. Travellers with IBD should be aware of the balance of risks between immunomodulators therapy and travel related infections.

Immunisation

• Patients with IBD taking immunomodulators (IMs) should be discouraged from visiting South American or sub-Saharan African countries where yellow fever is endemic, or yellow fever vaccine (a live attenuated vaccine) is required.

• Immunisation of patients with IBD against travel-associated vaccine-preventable diseases is highly desirable, given their altered immune status which predisposes them to infectious diseases and possible severe course of disease, once contracted.

• Live attenuated vaccines are contra-indicated in IBD patients on immunomodulator therapy (MMR,Typhoid Ty21a, Vaccinia, Yellow fever, live attenuated influenza vaccine, varicella, oral polio and BCG). Live-virus vaccines are probably safe in patients on less than 20 mg prednisone daily, or on higher doses provided they have been given for less than 14 days

• It is generally recommended that administration of live attenuated vaccines should be avoided for at least 3 months after treatment with immunomodulators is stopped. This delay may be reduced to 1 month in case of use of steroids alone. Immuno-modulator therapy should also be withheld for at least 3 weeks from the time of a live vaccine injection.

• Colectomy may impair the acquisition of immunity following oral administration of S. Enteritidis serovar Typhi Ty21a vaccine, but not oral inactivated Cholera vaccine. Immunisation with parenteral S. typhi Vi polysaccharide is preferred in patients with inflammatory bowel disease who have had a colectomy

• All patients with IBD should have Hepatitis A vaccination according to guidelines for the general population before travel to endemic areas. Response to Hepatitis A immunisation in immunocompromised patients with inflammatory bowel disease is unknown. Monitoring the acquisition of immunity by repeat serologic assays should be considered

The CDC does not take a position on the safety to the parent receiving immuno modulators whose child is vaccinated. This is not that uncommon in patients with IBD, when the mother or father of a baby due to have MMR may be receiving steroids, azathioprine or other IMs. However, no case of measles has been reported in such circumstances. Varicella live virus vaccine is probably safe in patients who have stopped thiopurines or MTX for at least one week before and one week after vaccination although longer than a week’s cessation of thiopurines or MTX may be desirable.

Other precautions for travellers

Patients with IBD should pay greater attention to precautions regarding food and water during travel than normal. Travellers are also best advised to avoid swallowing water while swimming in water that may be contaminated.

The immunocompromised patient should have a low threshold for initiating self-therapy for traveler’s diarrhoea with quinolones or azithromycin, but not rifaximin. If diarrhoea does not improve within 48 h despite treatment, medical advice should be sought.

Traveller’s diarrhoea, which may be severe and incapacitating, is the most common health problem reported during travel to developing countries. The duration is usually 1 to 5 days, but 5–10% of travellers report diarrhoea that lasts for 2 weeks or longer, and 1–3% report diarrhoea that lasts four weeks or longer. It is unknown if patients with IBD are at higher risk for acquiring traveller’s diarrhoea. However, this common disease, particularly if prolonged, may lead the traveller or the clinician to a wrong diagnosis of an exacerbation of IBD and to unnecessary self-treatment with medication for IBD.

Travellers to developing countries are often advised to carry a fluoroquinolone for empirical self-treatment of traveller’s diarrhoea. Azithromycin, which was found to be comparable to quinolones should be considered for self-treatment of traveller’s diarrhoea in the following situations:

(i) patients who take a fluoroquinolone as part of their treatment for IBD

(ii) Travellers to countries where endemic bacteria are known to have high levels of fluoroquinolone resistance (e.g. Thailand and India)

(iii) Patients who have no response to a quinolone within 36–48 h

(iv) Pregnant women and children <16 years (for whom a fluoroquinolone is contraindicated).

Rifaximin was approved for the treatment of traveller’s diarrhoea caused by non-invasive strains of E. Coli in patients aged >12 years. Rifaximin should not be used in patients with bloody diarrhoea or fever, or in patients who are

suspected of having traveller’s diarrhoea due to pathogens other than E. coli since rifaximin lacks efficacy against invasive pathogens (e.g. Shigella, Salmonella, and Campylobacter sp.). Since traveller’s diarrhoea among patients with IBD has not been studied and IBD travellers may not themselves be able to determine the aetiology of their diarrhoea, empirical self therapy with rifaximin cannot be advocated at this stage. The immunocompromised traveller should have a lower threshold than immune competent travellers for initiating self-therapy for traveller’s diarrhoea.

Screening for latent tuberculosis

The risk of M. tuberculosis infection in long-term travelers to countries with high-endemicity is of similar magnitude to the average risk of the local population. Patients with IBD traveling for more than a month to a moderately or highly endemic area should be advised to have a tuberculin skin test or interferon-gamma release assay (IGRA) before departure. If negative, it should be repeated approximately 8–10 weeks after returning. Caution should be exercised in recommending IGRAs, since the predictive value in the immunocompromised is uncertain. Patients with inflammatory bowel disease on immunomodulators should avoid contact with TB patients.

Malaria

Unless pregnant, asplenic, or concomitant HIV infection, patients with IBD appear not to be at higher risk for acquiring malaria or the more severe complications of malaria compared to travellers without IBD, even when taking immunomodulators. Recommendations for malaria prevention, including prevention of mosquito bites and chemoprophylaxis, should be followed according to the existing guidelines. Interactions between antimalarial drugs and drugs for the treatment of IBD, particularly those that are new, should be taken into consideration.

Prevention of insect bites

Immunocompromised IBD travellers should take extra precautions to prevent bites of insects that are known to transmit diseases that are particularly severe in immunocompromised patients. Examples include reduviid bugs in rural Brazil and sandflies on beaches in exotic locations,which are the vectors of Chagas’ disease and visceral leishmaniasis respectively. Patients taking immunomodulators

should also be aware that infestation with scabies may lead to a severe variant (Norwegian, or crusted scabies) that is often complicated by secondary bacterial infection.

General investigations

Long term travellers with inflammatory bowel disease returning from developing countries should have a stool examination for bacterial pathogens, ova and parasites and a complete blood count to identify eosinophilia. For long term travellers with inflammatory bowel disease returning from countries highly endemic for strongyloidiasis, serological blood test for strongyloidiasis should be considered. Many experts recommend therapy for seropositive patients, even if stool examinations are negative

9. Vaccination and systematic work-up to consider before introducing immunomodulator therapy

9.1. Detailed interview

Ideally the medical history should cover:

• History of bacterial infections (especially urinary tract infection)
• History of fungal infections
• Risk of latent or active tuberculosis:
  • date of the last BCG vaccination
  • potential contact with patients having tuberculosis
  • country of origin, or prolonged stay in an area endemic for tuberculosis
  • history of treatment for latent or active tuberculosis
• History of varicella-zoster virus infection (chickenpox/ shingles)
• History of herpes simplex virus infection
• Immunisation status for hepatitis B
• History of travel and/or living in tropical area or countries with endemic infections
• Future plans to travel abroad to endemic areas.

9.2. Physical examination

General physical examination best includes a search for features that often pass without comment, because they are of minor significance in people who are generally healthy, but which may have substantial implications when immunosuppressed:

• Systemic or local signs of active infection (including gingivitis, oral or vaginal candidiasis, or intertrigo as features of fungal infection)
• Cervical smear.

9.3. Laboratory tests

Many opportunistic infections are preventable and the potential for severe infection during immunosuppression can be ameliorated if thought is given to identifying risks before starting immunomodulator therapy. Ideally, baseline tests, potentially performed at diagnosis, should include:

• Neutrophil and lymphocyte cell count
• C-reactive protein
• Urine analysis in patients with prior history of UTI or urinary symptoms
• Varicella zoster virus (VZV) serology in patients without a reliable h/o of varicella immunisation
• Hepatitis B virus serology
• Human immunodeficiency virus (HIV) serology after appropriate counselling
• Eosinophil cell count, stool examination and strongyloidiasis serology (for returning travellers).

9.4. Screening for tuberculosis

Screening for tuberculosis should be considered before using high dose corticosteroids or immunomodulators other than anti-TNF therapy, although it is considered mandatory for the latter group.

• Clinical context of risk (gathered from a detailed history, above)
• Chest radiograph
• Tuberculin skin test or interferon gamma release assay.

9.5. Vaccination

Vaccines are best given before introduction of immunomodulators therapy. Consideration could reasonably be given to a vaccination programme at diagnosis of IBD, since around 80% of patients will be treated with corticosteroids, 40% with thiopurines and 20% with anti-TNF therapy.

As in the general population, the immunisation status of patients with inflammatory bowel disease should be checked and vaccination considered for routinely administered vaccines: tetanus, diphtheria, poliomyelitis. In addition, every patient with IBD should be considered for the five following vaccines, ideally at diagnosis for the reasons above:

• VZV varicella vaccine (if there is no medical history of chickenpox, shingles, or VZV vaccination and VZV serology is negative
• Human papilloma virus
• Influenza (trivalent inactivated vaccine) once a year
• Pneumococcal polysaccharide vaccine
• Hepatitis B vaccine in all HBV seronegative patients.

Vaccines for patients on immunomodulators travelling in developing countries or frequently travelling around the world should be discussed with an appropriate specialist.

Ref:

http://www.ecco-ibd.eu/images/stories/docs/guidelines/oi_eccoconsensus.pdf

• A Cochrane review showed that methotrexate (25 mg/week) injected intramuscularly for 16 weeks among patients with active treatment resistant Crohn’s disease may be an effective treatment.
• Lower doses of methotrexate (12.5 to 15 mg/week) taken orally are not effective treatment for Crohn’s disease.
• There is also evidence that methotrexate reduces the need for steroid treatment. This reduction in steroid use could reduce steroid induced side effects for people with chronic Crohn’s disease.
• The mechanism by which it improves inflammatory bowel disease is not certain.
• There is no evidence of it being effective in UC.

Discuss the side effects of methotrexate?

• GI toxicity- nausea, vomiting, diarrhoea, and stomatitis. This may be limited by co-prescription of folic acid (1mg/day).
• Hepatotoxicity- Withhold MTX if the aminotransferases doubles. Rechallenge may be attempted once LFTs normalise. Surveillance liver biopsy based upon the cumulative dose of MTX is not recommended. Use of MTX should be carefully considered in patients who are obese, diabetic and those who consume excess alcohol as the risk of hepatotoxicity may be increased.
• Pneumonitis-This is rare.

Discuss the monitoring needed during methotrexate use?

Measurement of full blood count and liver function tests are advisable before and within 4 weeks of starting therapy, then monthly.

Discuss methotrexate in pregnancy?

Methotrexate is absolutely contraindicated as it is a potent abortifacient and is associated with congenital anomalies. Women and men taking methotrexate should stop this drug and use contraception for at least three months prior to conception.

Acute severe colitis not responding to steroids

• Rescue therapy with ciclosporin could be considered on the third day of intensive treatment if predictive factors are poor (>8 bloody stools, or 3-8 bloody stools and CRP>45).
• Ciclosporin is suitable for patients with persistent severe colitis after 7 days of intravenous steroids who do not need immediate colectomy

Discuss the mechanism of action of ciclosporin?

It is a lipophilic 11-amino acid cyclic peptide of fungal origin with strong immunosuppressive actions thatacts primarily through inhibition of T-helper cells by binding to cyclophilin (cytosolic protein). This ciclosporin-cyclophilin complex binds to and inhibits calcineurin, a calcium dependent protein phosphatase required for the activation of transcription factors used in early cytokine production. In particular interleukin 2 (IL-2), a cytokine required for T cell activation and proliferation is blocked

Discuss the dose of ciclosporin?

2mg/kg/day by continuous IV infusion (continue up to 7 days depending on the response).
Some centres use oral ciclosporin 5-8mg/kg/day in 2 divided doses with small studies suggesting that oral ciclosporin has the same efficacy and toxicity as the intravenous form.

Discuss the contraindications for ciclosporin use?

• Moderate to severe renal impairment (creatinine > 130 micromol/litre or 20-30% reduction in eGFR)
• Current malignancy (previous malignancies may also be a contraindication).
• Current infection.
• Uncontrolled hypertension
• Immunodeficiency

Discuss the tests needed before using ciclosporin?

Check the renal function, LFTs, magnesium and cholesterol.

Discuss magnesium and cholesterol?

The risk of seizures is increased in patients with a low cholesterol (<3.0 mmol/l) or magnesium (<0.50 mmol/l). Oral therapy is an alternative in these circumstances. Microemulsion ciclosporin does not contain the chromophore present in intravenous ciclosporin that has been associated with neurotoxicity causing seizures in patients with hypocholesterolaemia or hypomagnesaemia.

• Monitoring
• Check ciclosporin levels on day 2 and then every 3 days (aim for trough levels of 150-250 ng/ml).
• Monitor U&E, LFT, Mg and Cholesterol on alternate days.
• Reduce the ciclosporin dose by 25% if any of these occur
• serum creatinine rises by more than 30% from baseline
• SBP is > 150mm Hg or DBP exceeds 90 mm Hg despite antihypertensive treatment.
• Serum liver enzymes double
• Hypertension is treated with a calcium channel blocker such as nifedepine, because it may offer protection against ciclosporin induced nephrotoxicity. However the use of calcium channel blockers can lead to a rise in serum ciclosporin levels, so careful drug level monitoring is essential.

Discuss conversion to oral ciclosporin?

Once response occurs IV ciclosporin is converted to oral ciclosporin in 2 divided doses. An oral dose of 5mg/kg/day is equivalent to 2mg/kg/day intravenous dose since the oral bioavailability of neural (ciclosporin) is 30-40%. However the blood levels need to be monitored and the dose titrated accordingly. For patients who are not on an immunomodulator (azathioprine or 6-mercaptopurine) oral ciclosporin should be continued for 3 months whilst an immunomodulator is introduced.

Discuss ciclosporin levels?

The levels could be done at anytime during the 24 hr infusion. Trough levels are needed once the patient is on oral ciclosporin. Aim for ciclosporin levels of 150-250 ng/ml.

Discuss PCP prophylaxis?

PCP prophylaxis with Co-trimoxazole (960mg 1 tab administered three times per week) should be considered especially with triple immunosuppression (steroids, azathiopurine and ciclosporin)

Discuss the side effects?