1.1. 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.

1.2. 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.

1.3. 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).

1.4. 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.

1. Clinical context of risk (gathered from a detailed history, above)
2. Chest radiograph within 3 months of starting therapy
3. Interferon gamma release assay.

If any of the above 1, 2 or 3 is positive, the patient should be referred for assessment  to a specialist with an interest in TB. If IGRA is indeterminate or equivocal, it could be repeated after 2-3 weeks and if still indeterminate or equivocal- the patient should be referred for assessment to a specialist with an interest in Tb

1.5. 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.

1.6 Other precautions

• Exclude Pregnancy
• Contraception during and 5 months (for Humira) after stopping the treatment- if pregnant need to report to Manufacturer’s registry.
• Not to breast feed (breast feeding is a contraindication for biologics)
• Monitor FBC/LFT/Urea electrolytes every week for a month, then twice monthly and then monthly
• Previous history of neurological disease (caution should be exercised when using biologics for patients with h/o CNS demyelinating disorders)
• Previous history of cancer
• H/o Cardiac failure (biologics are contraindicated in moderate to severe heart failure, exercise caution with mild heart failure)

Ref:

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

Five to ten per cent of Tuberculin skin test (TST) positive individuals will progress from this clinically asymptomatic state (here termed latent TB infection (LTBI) to active disease. The use of anti-TNF? agents increases the risk of LTBI progressing to active TB by approximately fivefold. This is often rapid and aggressive, occurring at a median of 12 weeks from anti-TNF? initiation in the earliest reports. Thus, the onset of new respiratory symptoms, particularly within 3 months of commencing anti-TNF treatment, should be investigated promptly

Thus, all patients should be screened for latent TB before initiating anti-TNF treatment.

How to diagnose latent tuberculosis?

All patients should have:

1. Careful history: Previous h/o TB or TB treatment
2. CXR: within 3/12 of starting biologics. An abnormal chest radiograph suggestive of old TB (calcification >5 mm, pleural thickening, or linear opacities) should also be considered suggestive of latent TB even if other criteria are absent.
3. TB IFN? release assays (IGRA)

If any of the above 1, 2 or 3 is positive, the patient should be referred for assessment to a specialist with an interest in TB. If IGRA is indeterminate or equivocal, it could be repeated after 2-3 weeks and if still indeterminate or equivocal- the patient should be referred for assessment to a specialist with an interest in Tb

Discuss the treatment of latent TB?

There are two potential chemoprophylaxis regimens: isoniazid for 6 months (6H) or rifampicin plus isoniazid for 3 months (3RH).

It should be noted that no chemoprophylaxis regimen is wholly effective; protective efficacies of 60% have been reported for 6H and of 50% for 3RH. If patients who have had chemoprophylaxis develop symptoms suggestive of clinical TB, they should be promptly and appropriately investigated.

Discuss monitoring with latent TB treatment?

Isoniazid-related hepatotoxicity occurs in approximately 0.15% of patients. It may occasionally be severe and life threatening.  Minor transaminase elevations (3-fold) are common (10–20%) during isoniazid therapy and of no consequence.

Most advise monitoring liver function at intervals, with cessation or alteration of therapy if the transaminases exceed >3-fold elevation associated with hepatitis symptoms or jaundice, or >5-fold in the absence of symptoms.

If a patient needs to start Latent TB treatment, when can they safely start anti-TNF? agents?

Patients with active TB should receive a minimum of 2 months full chemotherapy directed by a specialist in TB before starting anti-TNF-a treatment.

Discuss the disadvantages of TST?

• Diagnosis of latent TB by TST may be distorted by prior BCG vaccination, because vaccinated individuals may become positive reactors to purified protein derivate (PPD). This distortion is almost insignificant in adults >30 years of age, irrespective of age at vaccination or re-vaccination.
• TST may also be negative in patients on steroids (>20mg/day) for >1 month, or thiopurines or methotrexate for >3 months. The TST cannot adequately be interpreted if corticosteroids are not discontinued for >1 month and immuno modulators for >3 months.
• A false negative TST may also occur during active IBD without immuno suppression.

Thus, NICE recommends an interferon-gamma test in immunosuppressed patients and in BCG vaccinated people

Discuss IFN? release assays (IGRAs) tests for TB?

Principle: T cells of individuals who have been exposed to TB (and hence its antigens) will produce IFN? when they are re-challenged with mycobacterial antigens contained within the test kit.

Mycobacterial antigens used for the test: ‘early secretion antigen target 6? (ESAT-6), ‘culture filtrate protein 10? (CFP-10) and tb7.7. These antigens are not present in BCG, and are found in only a few species of environmental mycobacteria.

Tests available: There are currently three interferon-gamma immunological tests commercially available: QuantiFERON-TB Gold, QuantiFERON-TB Gold In tube and T-SPOT.TB.

QuantiFERON-TB Gold measures the release of interferon-gamma in whole blood in response to stimulation by ESAT-6 and CFP-10. The In tube version measures ESAT-6, CFP-10 and tb7.7.

T SPOT-TB measures IFN? production (using ESAT-6 and CFP-10 antigens) from a fixed number of blood mononuclear cells via an ex vivo overnight enzyme linked immunospot (ELISPOT) assay.

Results: Each time that a test is run on a blood sample, a negative control (which contains no stimulating antigen) and a positive control (with mitogen) are also tested against the blood sample. Indeterminate results occur when either the negative control records a positive result, (i.e., the blood sample’s T cells release IFN? without specific stimulation) or the mitogen does not stimulate the cells as expected (and no IFN? is produced). Indeterminate results are particularly common in the populations where a clear-cut result would be most helpful, such as the immunosuppressed, patients in an intensive care unit, children and older adults.

Advantages of IGRA tests over TST:

Results are usually available within 24–48 h

More specific than the TST in BCG-vaccinated populations

No follow-up visit is required

More sensitive and specific than TST

References

1. British Thoracic Society Guidelines (hyperlink to

http://www.brit-thoracic.org.uk/Portals/0/Clinical%20Information/Tuberculosis/Guidelines/antitnf.pdf

2. Greveson K et al . Interferon ?-release assays for detecting latent tuberculosis infection in patients scheduled for anti-TNF? therapy. Frontline Gastroenterology 2011;2:26–31. doi:10.1136/fg.2009.000356

3. NICE guidance 2011 (link it to http://www.nice.org.uk/nicemedia/live/13422/53638/53638.pdf

Side effects include:

• Injection site reactions
• Infusion reactions
• Demyelinating disease
• Heart failure
• Malignancy
• Induction of autoimmunity
• Hepatotoxicity
• Cytopenias
• Infections.

Injection site reactions – are common but usually minor problems.

Infusion reactions

• Causes non specific symptoms, but true anaphylaxis can occur.
• Majority of infusion reactions are acute (usually within 4 hrs) occurring within 24 hrs.
• Delayed reactions can develop between 1-14 days after the start of treatment.
• Use of concurrent immunomodulators reduces the risk of infusion reactions.
• Acute infusion reactions can be treated by stopping the infusion temporarily, hydration and using antihistamines. Severe/anaphylactic reactions will need steroids and epinephrine. Delayed infusion reactions can be treated with paracetamol and antihistamines.
• Preventive strategies include:
  • Premedication with antihistamines ninety minutes prior to infusion.
  • Use of a test dose of IFX.
  • IV hydrocortisone with antihistamines before infusion in patients with a previous severe reaction.

Demyelinating disease

• An unproven link between TNF inhibitors and demyelinating disease has been suggested. Thus, use of anti- TNF agents in patients with demyelinating diseases like MS should be avoided. Some experts also advice caution in patients with family histories of MS.
• Anti-TNF therapy should be discontinued immediately in any patient with suspected demyelination.
• Symptoms of demyelination reported with the use of TNF inhibitors included confusion, ataxia, dysesthesia, and paresthesia.
• Neurologic findings included facial nerve palsy, optic neuritis, hemiparesis, transverse myelitis, and ascending motor neuropathy consistent with the Guillain-Barré syndrome.
• All neurologic events had a temporal relationship to anti-TNF therapy, and all improved partially or completely upon discontinuation of such therapy.

Heart failure

• TNF inhibitors use has been associated with new or worsening of pre existing heart failure.
• TNF inhibitors should be used with caution in patients with HF or decreased left ventricular function.
• Further, infliximab is contraindicated at doses higher than 5 mg/kg in patients with moderate or severe HF (NYHA class III/IV).

Hepatotoxicity

TNF inhibitors may cause hepatitis, cholestasis or acute liver failure but the risk is small.

Cytopenias

There are rare reports of pancytopenia and aplastic anaemia associated with TNF inhibitors. Monitoring of patients’ blood cell counts every few months is therefore appropriate.

Malignancy

• There is increased risk of lymphomas in patients receiving TNF inhibitors.
• Data on the risk of solid malignancy as a complication of TNF inhibitor use is mixed.
• Further, small case series suggest an increased risk of nonmelanoma and melanoma skin cancers among patients treated with TNF inhibitors.
• Hepatosplenic T-cell lymphoma (HSTCL) has been reported with infliximab use in paediatric and young adult patients. In all cases, patients also received other immunosuppressive agents, including thiopurines. Reports of HSTCL occurring in Crohn’s disease patients receiving these drugs without infliximab have also been published. Thus, a causal relationship between infliximab and the development of HSTCL cannot be clearly established.

Autoimmune diseases and neutralising antibodies

• Use of biologics lead to the formation of neutralizing antibodies. This is clinically important as it may lead to allergic reactions or loss of efficacy.   This is less of a problem with adalimumab, because the antibody is fully humanized.  Concomitant immuno modulator use leads to reduced incidence of neutralizing antibodies.
• Autoantibodies- TNF inhibitor treatment is associated with an increased incidence of developing antinuclear antibodies (ANA) or antibodies to double-stranded DNA (anti-DNA antibodies).
• Autoimmune diseases- a small minority of patients treated with TNF inhibitors develop autoimmune conditions (vasculitic or lupus like syndromes) as a result of their therapy.  Most of these syndromes resolve following discontinuation of the TNF inhibitor.
• Other reported autoimmune diseases (link unclear)-  interstitial lung disease (ILD) and uveitis

TNF inhibitors and tuberculosis

• TNF inhibitors increase the risk of reactivation of latent TB infection (LTBI).   TB occurring in association with TNF inhibitors is more likely to be extra pulmonary or disseminated at presentation.  Cases of TB that occur soon (within 90days)  after the initiation of a TNF inhibitor are likely to represent reactivation of latent TB infection, whereas those that occur later may represent either inefficient reactivation or newly acquired TB infection progressing directly to active disease.
• Prevention- all patients should be screened for LTBI prior to starting a TNF inhibitor.  Appropriate screening includes a full medical history, physical examination, tuberculin skin test (TST) or interferon-gamma release assay (IGRA), and a chest x-ray in those with a positive TST (>5mm) or IGRA or a history or physical exam suggestive of TB.
• Management – LTBI should be treated prior to starting a TNF inhibitor. The CDC recommends treatment for LTBI if the TST or IGRA is positive or if there is evidence of remote TB disease on CXR (e.g., regional fibrosis) or if there is epidemiologic evidence of prior TB exposure (eg, having had close contact to a TB case, or having resided in a country of high TB incidence) even if TST or IGRA are negative.
• LTBI treatment- isoniazid (300mg OD) for nine months. Patients should receive at least 1-2 months of LTBI treatment before starting anti-TNF therapy whenever possible.
• Active TB – TNF inhibitors should be discontinued in patients who develop active TB until an antituberculous regimen has been started and clinical improvement is evident
• Disease worsening during TB treatment – Discontinuation of a TNF inhibitor in the setting of reactivation of LTBI may be associated with a paradoxical worsening of TB. The basis for this is hypothesized to be an immune reconstitution inflammatory syndrome (IRIS). In such cases, the use of glucocorticoids may be beneficial. Some have suggested that the resumption of TNF inhibitors may be indicated, but this remains controversial.

Infections

• The risk of bacterial, viral and fungal infections is increased with TNF inhibitor treatment. The risk of infection associated with TNF inhibitor use is highest in the period shortly after the initiation of therapy.
• Hepatitis B – reactivation may occur. Prophylactic treatment may be considered in patients starting infliximab therapy.
• HIV- TNF inhibitors can be well tolerated by HIV-infected patients, provided that treatment of HIV is well established before initiation of therapy with a TNF inhibitor.
• Biologics may also cause Pneumocystis carinii pneumonia (PCP). PCP prophylaxis should be considered among patients treated with TNF inhibitors if they are also receiving high-dose glucocorticoids or other intensive immunosuppression.
• Patient education about the importance of recognizing symptoms and signs of infections particularly fever is vital. These patients should be assessed without delay because of the likelihood of disseminated infections.

Vaccines – live vaccines should NOT be administered during treatment with TNF inhibitors.

NICE (2010) recommendations for use of biologics

When to use?

Infliximab and adalimumab are recommended as treatment options for adults with severe active Crohn’s disease or active fistulising Crohn’s disease,  whose disease has not responded to conventional therapy (including antibiotics, drainage, immunosuppressive and/or corticosteroid treatments), or who are intolerant of or have contraindications to conventional therapy.

How long to use?

Infliximab or adalimumab should be given as a planned course of treatment until treatment failure (including the need for surgery), or until 12 months after the start of treatment, whichever is shorter.

Should treatment be stopped at 12 months?

People should then have their disease reassessed to determine whether ongoing treatment is still clinically appropriate. Treatment with infliximab or adalimumab should only be continued if there is clear evidence of ongoing active disease as determined by clinical symptoms, biological markers and investigation, including endoscopy if necessary.

People who continue treatment with infliximab or adalimumab should have their disease reassessed at least every 12 months to determine whether ongoing treatment is still clinically appropriate. People whose disease relapses after treatment is stopped should have the option to start treatment again.

Which biologic to use: infliximab or adalimumab?

Treatment should normally be started with the less expensive drug (taking into account drug administration costs, required dose and product price per dose). The costs will vary depending on local arrangement

Discuss the treatment regime?

Define severe disease as discussed in NICE guidance?

• Severe active Crohn’s disease is defined as very poor general health and one or more symptoms such as weight loss, fever, severe abdominal pain and usually frequent (3–4 or more) diarrhoeal stools daily.
• People with severe active Crohn’s disease may or may not develop new fistulae or have extra-intestinal manifestations of the disease.
• This clinical definition normally, but not exclusively, corresponds to a Crohn’s Disease Activity Index (CDAI) score of 300 or more, or a Harvey-Bradshaw score of 8 to 9 or above.
• The CDAI is frequently used to assess disease severity. It is a composite of overall activity of Crohn’s disease as assessed by clinicians, and has eight variables weighted according to their ability to predict disease activity. It gives a score ranging from 0 to over 600, based on a diary of symptoms kept by the patient for 1–7 days, and other measurements such as the patient’s weight and haematocrit. A CDAI score of less than 150 is considered to be remission, a score greater than 220 is considered to define moderate to severe disease, and a score greater than 300 is considered to be severe disease. The paediatric CDAI (PCDAI) is an instrument similar to the CDAI but with less emphasis on subjectively reported symptoms and more emphasis on laboratory parameters of intestinal inflammation.
• The Harvey-Bradshaw Index is another commonly used tool, which correlates well with CDAI. It is based on assessments of general wellbeing, abdominal pain, number of diarrhoeal stools per day, and the presence of abdominal mass and associated complications. Patients with a score of 8 to 9 or higher are considered to have severe disease.

Discuss paediatric use of biologics?

Infliximab, within its licensed indication, is recommended for the treatment of people aged 6–17 years with severe active Crohn’s disease whose disease has not responded to conventional therapy (including corticosteroids, immunomodulators and primary nutrition therapy), or who are intolerant of or have contraindications to conventional therapy. The need to continue treatment should be reviewed at least every 12 months.

Fistulising Crohn’s disease: For people aged 6–17 years, infliximab is given as a 5-mg/kg intravenous infusion followed by additional 5-mg/kg doses at 2 and 6 weeks after the first dose, then every 8 weeks thereafter.

NICE guidance: TA187 Crohn’s disease – infliximab (review) and adalimumab (review of TA40)

http://www.nice.org.uk/nicemedia/live/12985/48552/48552.pdf

• Moderately to severely active Crohn’s disease that is refractory to conventional therapy.
• Fistulising Crohn’s disease that is refractory to conventional therapy

Clinical trials have demonstrated significant utility of infliximab for induction of remission in moderately active, steroid refractory Crohn’s disease, improvement in quality of life, and maintenance of remission in these patients for up to 54 weeks after initial infusion.

How?

2 strategies

• Scheduled maintenance- Dose 5mg/kg. Induction doses at 0,2 and 6 weeks and then retreatment of patients who respond to initial therapy every four- to eight-week interval at 5 mg/kg  depending upon how quickly relapse of the Crohn’s disease symptoms occurs.
• Episodic use- on demand retreatment with 5 mg/kg after a single inductive infusion of infliximab. Inductive infusion is at 0, 2 and 6 weeks for fistulising Crohn’s disease and then on demand retreatment.

Discuss episodic treatment? (NICE recommends episodic treatment)

• Safety and cost are important aspects of all drug usage.  Toxicity is not substantially enhanced and infusion reactions are not decreased by regularly scheduled infusions.
• Drug costs tend to decrease with time and competition and thus should not be used as a major reason for opting for an episodic regime. Further considering the costs of surgery and hospitalisations, a maintenance regime of infliximab is cost effective.
• In ACCENT I study, the authors stress the clinical superiority of the scheduled maintenance treatment groups over the episodic strategy, with significant advantages in remission and response rates, quality of life, mucosal healing, Crohn’s disease related hospitalizations, and intra-abdominal surgery. However, regularly scheduled administration of the FDA-approved dose of 5 mg/kg infliximab was significantly better than episodic infusion in only 2 parameters (hospitalization, 23% vs. 38%; P =0.047; intra-abdominal surgeries, 3% vs. 7%; P =0.04).
• Remission and response are the most widely accepted outcome measurements for Crohn’s disease clinical trials. ACCENT I-  only a minority of patients (44%) in the 5-mg/kg regularly scheduled group completed the study as designed; 26% discontinued treatment without crossover and 30% were crossed over to 10 mg/kg “rescue” therapy. Therefore, an alternative interpretation of these results is that on-demand retreatment with 5 mg/kg after a single inductive infusion of infliximab is comparable to the more expensive strategy of 3 inductive infusions followed by scheduled treatments every 8 weeks.
• Certainly, a patient with luminal Crohn’s disease who requires infliximab treatment and who is not yet on immunosuppressant drugs can be induced with a single infliximab infusion after beginning maintenance 6MP, azathioprine, or methotrexate, thereby reserving regularly scheduled infliximab infusions for those patients failing optimal immunosuppressant maintenance treatment.

Discuss management strategy of patients who initially respond but then lose their response?

Antibodies to infliximab reduce infliximab blood levels and causes loss of response. This can be overcome by 4 different strategies;

• decrease the intervals between re infusions to 7, 6, 5, or 4 week intervals
• increase the infliximab dose to 10 mg/kg
• Both
• Switch to adalimumab

Discuss efficacy of infliximab treatment?

Adalimumab

Discuss dosing?

The approved induction dosing of adalimumab in Crohn’s disease is 160 mg given subcutaneously initially at week zero, 80 mg at week two, followed by a maintenance dose of 40 mg every other week beginning at week four. The drug is available in a single-use prefilled pen (HUMIRA Pen)

Discuss the efficacy?

Patients generally respond within the first week. Responses were maximal by three doses in the CLASSIC and CHARM studies. Patients who do not respond within this interval should not continue adalimumab.

Efficacy similar to Infliximab

Discuss the indications?

• Same as Infliximab
• Adalimumab can be used in patients who had lost response to or are intolerant of infliximab. Used as such in GAIN study, adalimumab was more effective than placebo at achieving clinical remission (21 versus 7 percent) and response (38 versus 25 percent)

Dosing of Adalimumab:

Starting Dose:

On day 1* 4 (four 40 mg) injections of HUMIRA. (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days)
On day 15 2 (two 40 mg) injections of HUMIRA.

Continuing Dose:

On day 29 1 (one 40 mg) injection of HUMIRA.
After day 29 regular scheduled dose of one Pen (40 mg) every other week.

How to use the pen:

http://www.myhumira.com/Administering/Instructions.aspx?p=pen

How to use the syringe:

http://www.myhumira.com/Administering/Instructions.aspx?p=syringe

Patient information about Adalimumab: from NACC website

http://www.rxabbott.com/pdf/humira_medguide.pdf

Breast feeding and Adalimumab?

As the long-term effects of adalimumab on a child’s developing immune system are still not known, it is recommended that patient should not breast-feed during treatment or for six months after last dose.

Does adalimumab affect pregnancy?

There have been several reports of successful pregnancies in women with Crohn’s on adalimumab before conception or during pregnancy. Because the drug is relatively new the clinical evidence is limited therefore, the manufacturers recommend that woman of childbearing age should use adequate contraception to prevent pregnancy and continue to use it for at least 5 months after stopping taking adalimumab.

However, in many cases the risks of active Crohn’s disease outweigh the risks of the drug, even during pregnancy. In severe Crohn’s disease when patient  do not want to wait before trying for a baby the doctor and the patient together will have  to weigh up the risk of stopping against the benefits of continuing with treatment.

If the patient becomes pregnant while using adalimumab there may be reasons to continue throughout the first 6 months of pregnancy. In the last 3 months of pregnancy adalimumab should only be used with caution as it will cross the placenta and might affect the immune system of baby.

• Steroid dependent or refractory IBD
• Fistulating and perianal CD
• Maintenance treatment- effective for maintaining remission for many years in up to 95 percent of patients with Crohn’s disease whose remission was initially achieved with these drugs.

Discuss the pharmacology of thiopurines?

• Azathioprine is a pro drug which undergoes conversion to 6-MP.  The conversion is done non-enzymatically by glutathione present in red blood cells and other tissues.
• 6-MP is then metabolized in the liver and gut by one of three enzymes; 6-thiopurine methyl transferase (TPMT), Xanthine oxidase, and Hypoxanthine-guanine-phosphoribosyl transferase (HGPRT).  HGPRT converts 6-MP to active metabolite 6-thioguanine (6-TG) nucleotides whereas the other two enzymes metabolises 6-MP to inactive metabolites.

Discuss the mechanism of action of thiopurines?

The precise mechanism is unknown. It appears likely that their thioguanine nucleotide metabolites modify the immune response by inhibiting DNA synthesis in T-lymphocytes. Interference with neutrophil function may also be important.

Discuss the dosage for thiopurines?

• Azathioprine- maximum dose of 2.5mg/kg body weight

6-MP- maximum dose 1.5 mg/kg body weight

• These drugs (AZA or 6-MP) are generally started at 50 mg. If the medication is well tolerated after one month, then the dose of 6-MP is increased to 75 mg and AZA is increased to 100 mg, depending on the patient’s weight. After three months of therapy, the dose of 6-MP and AZA may be further increased to 100 mg and 150 mg, respectively, if no obvious therapeutic response is seen, provided that the patient is tolerating the therapy and the WBC is > 4 X 10(3)/L.
• A minimum effective dose for inducing remission is unknown. Further, whether leukopenia is needed to induce a response is controversial.
• Allopurinol blocks the metabolism of 6-MP by inhibiting xanthine oxidase and so in these patients, it is often adequate to use half doses of AZA or 6-MP.

Discuss the efficacy of thiopurines in maintaining remission?

A Cochrane review concluded that

• The Peto odds ratio (OR) for maintenance of remission with azathioprine was 2.32 (95% CI 1.55 to 3.49) with a NNT of 6.
• The Peto OR for maintenance of remission with 6-mercaptopurine was 3.32 (95% CI 1.40 to 7.87) with a NNT of 4.
• Higher doses of azathioprine improved response.
• A steroid sparing effect with azathioprine was noted, with a Peto OR of 5.22 (95% CI 1.06 to 25.68) and NNT of 3 for quiescent disease.
• A benefit on induction of remission has also been suggested but the magnitude of benefit is unclear, particularly since several months of treatment are required before maximal efficacy is observed.

Discuss the time to response for thiopurines?

These are slow acting drugs and take 3-6 months to exert their effect. Thus these drugs are not indicated for monotherapy in acute relapses of inflammatory bowel disease.

Discuss the use of azathioprine versus 6-MP?

There is greater published evidence with azathioprine, however they can be used for similar indications and are equally effective.  A proportion of patients intolerant of azathioprine (predominant GI side effects) can tolerate 6-MP. Azathioprine is generally preferred in UK.

How long the thiopurines should be continued??

It is generally recommended that therapy with AZA/6-MP who has achieved remission should be continued indefinitely, as long as the treatment is well tolerated. Some experts recommend stopping thiopurines after 4 years in view of the risk of malignancy with continued use of thiopurines.

Discuss the side effects of thiopurines?

• Common side effects- nausea, vomiting and malaise. Dyspeptic symptoms can be minimized by taking the drug with meals.
• Dose dependent such as bone marrow depression and liver dysfunction
• Dose independent including pancreatitis , allergic reactions such as drug fever or rash, and pneumonitis
• Infectious- patients should be watched carefully for opportunistic infections especially those on concomitant steroids
• Neoplastic – A meta-analysis estimated that the risk of lymphoma in patients with IBD treated with azathioprine or 6-MP was increased fourfold compared with the general population.

Discuss the monitoring needed during thiopurine treatment?

• A complete blood count with differential should be obtained weekly for the first month and then 3 monthly for as long as the patient is receiving therapy.

If the white cell count decreases below 4x 10(9)/L or the platelet count decreases below 120 x 10(9)/L, the dose should be reduced until these parameters normalize, while if the white blood cell count decreases below 3 x 10(9)/L or the platelet count decreases below 80 x 10(9)/L the drug should be discontinued until these parameters normalize.

• Liver function tests should be obtained every three months

A dose-dependent elevation in serum aminotransferases can occur. Mild hepatitis is usually reversed by lowering the drug dose by up to 50%.  Besides mild hepatitis, both 6-MP and AZA can cause severe cholestatic jaundice, which may progress despite discontinuing therapy. Thus, treatment should be stopped in patients who develop significant unexplained hyperbilirubinemia while on therapy.

Discuss the argument for testing for TPMT before initiating treatment with thiopurines?

• Toxicity of AZA or 6-MP is largely related to the activity of TPMT. Deficiency of TPMT leads to preferential metabolisation of 6-MP and AZA to thioguanine nucleotides responsible for much of the drug toxicity.
• Low TPMT activity has been observed in up to 11 percent (heterozygous) of the population, with 0.3 percent (homozygous) having negligible activity.
• Either TPMT genotype or TPMT enzyme activity can be measured. TPMT enzyme activity is often measured in clinical practice in UK
• Low TPMT enzyme activity may lead to increased risk of myelosuppression.  However, the majority of patients who develop myelosuppression while taking AZA do not have detectable TPMT gene mutations. Thus a normal TPMT screening test does not preclude bone marrow and/or liver toxicity.  Thus, even when TPMT testing is performed, regular FBC and liver function tests must still be obtained.
• Experts vary in their use of TPMT. However, in current clinical practice TPMT levels are often measured before initiating treatment. Those with absent TPMT enzyme activity should not receive AZA or 6-MP. Patients with normal TPMT enzyme activity can be treated either by beginning with a low dose and increasing incrementally to the target dose or by beginning with the target dose at the outset.
• In non responding patients 6-TG levels may be obtained to check compliance.

Discuss the safety of thiopurines in pregnancy and lactation?

• Both azathiopurine and 6MP are considered are safe in pregnancy.
• Reports of teratogenicity with these drugs have occurred in foetuses in which exposure was from either the mother or father. Males on 6-MP should probably stop the agent three months before conception to lessen the risks of spontaneous abortion and foetal abnormalities.

Azathioprine and 6-MP are detectable at low levels in breast milk. Mothers taking these drugs should avoid breast feeding, although no good data are available regarding risks to the nursing infant.

• Sulphasalazine consists of a sulfapyridine moiety attached to 5- aminosalicylic acid (5-ASA). It is broken down in the colon by the azoreductase bacterial enzyme to its individual components. 5-ASA is anti-inflammatory whereas sulfapyridine has antiarthritic and antibacterial properties. Sulfapyridine is also responsible for most of the side effects of Sulphasalazine. Sulfapyridine is rapidly absorbed from the colon, whereas 5-ASA is poorly absorbed from the colon.
• A number of 5-ASA products have been developed with similar efficacy to sulphasalazine but with better tolerance and side effect profile. Oral 5-ASA undergoes rapid absorption in the jejunum and will thus have limited efficacy in distal small and colonic disease. To bypass proximal small bowel absorption, delayed release formulations have been developed. This include topical formulations of mesalazine as enemas, suppositories or foams; oral mesalazine coated with various pH dependent polymers (asacol, salofalk); oral mesalazine encapsulated into ethylcellulose microgranules (Pentasa); or alternative azo bond derivatives that combine two 5- ASA moieties into a dimer (olsalazine, dipentum®); or attach 5-ASA to an alternative inert carrier (balsalazide, Colazide®). Olsalazine and balsalazide are mainly active in colon as they require colonic bacteria to cleave the azo bond and release the 5-ASA moiety. pH dependent polymers dissolve in pH greater than 7 and so releases the drug to the distal small bowel and colon.
• Recently a once a day formulation of mesalazine (Mezavant XL ®) has been released. It has a multimatrix system(MMX) that incorporates mesalazine into a lipophilic matrix within a hydrophilic matrix encapsulated in a polymer resistant to disintegration at a pH lower than 7 to delay release throughout the colon.
• Unencapsulated mesalazine granules (salofalk® granules) are also used.

Discuss the mechanism of action of aminosalicylates?

The exact mechanism is still unknown. However, their action is thought to be predominantly topical at the site of inflammation. Mesalazine have favourable anti-inflammatory effects in in vitro studies by reducing prostaglandin and leukotriene production, inhibiting bacteria induced chemotaxis and scavenging of free radicles.

Discuss the uses of aminosalicylates?

• Treatment and maintenance of remission in UC.
  • An effective dose (2 to 6 g/day) induces a remission in 50 to 80 percent of patients. The drug acts within 2-4 weeks. Sulphasalazine and 5-ASA drugs have similar efficacy but 5-ASA drugs have a better side effect profile.
  • Topical therapies (enemas, suppositories, foams) deliver mesalazine directly to the distal colon.  Topical therapies provide quicker response and are hence considered the treatment of choice for patients with distal colitis. The choice of formulation depends upon the extent of disease and patient preference. Suppositories are only effective in the rectum (about 10 cm), whereas enemas can reach the splenic flexure. However, enemas are more difficult to administer.
  • Combined oral and topical 5-ASA therapy is more effective than oral therapy or topical therapy alone in patients with more extensive mild to moderate UC.
  • 5-ASA also has a protective effect in prevention in colon cancer in UC.

• Use in Crohn’s disease
  • 5-ASA agents are used commonly for the treatment of mild to moderately active Crohn’s disease and for maintenance of remission. However their efficacy is not established in either role and some experts recommend that 5-ASA drugs should not be used in the treatment of Crohn’s disease for either induction or maintenance of remission. Others argue that 5-ASA should be used in patients with mild Crohn’s disease based upon their excellent safety profile.

Discuss the side effects of aminosalicylates?

• Sulfasalazine
  • Common side effects include nausea, headache, fever, rash, and male infertility. These problems are dose related.
  • Folic acid (1 mg/day) supplementation is recommended as sulphasalazine can affect folate metabolism.
  • Agranulocytosis is a rare side effect of Sulphasalazine. This typically occurs within the first two months of therapy and is almost invariably accompanied by fever and rash. Agranulocytosis may be fatal, although bone marrow recovery occurs in the majority of patients within one to two weeks of drug discontinuation.
  • Patients with sulpha allergies should not be given Sulphasalazine.

• Mesalazine
  • Headaches and gastrointestinal upset (nausea, abdominal pain) are the common side effects with mesalazine.
  • Diarrhea can occur with all mesalazine and 5-ASA preparations, especially those with a dia-azo bond, including olsalazine and balsalazide. Diarrhoea is due to increased ileal secretion and improves within a few weeks time due to colonic adaptation. In addition, mesalazine can rarely cause a paradoxical worsening of colitis symptoms.  This may be masked when patients are receiving concurrent steroids and may appear as refractory colitis. It is recommended that patients who are unable to taper steroids despite high dose mesalazine be given a trial off mesalazine to rule out unanticipated hypersensitivity colitis.
  • Renal impairment (including interstitial nephritis and nephrotic syndrome) is rare and idiosyncratic. All aminosalicylates have been associated with nephrotoxicity, which appears both to be idiosyncratic and in part dose related. Reactions are rare, but patients with pre-existing renal disease are at higher risk. Occasional (perhaps annual) measurement of creatinine is sensible, although there is no evidence that monitoring is necessary or effective. Aminosalicylates should be stopped if renal function deteriorates
• Hypersensitivity reactions to both Sulphasalazine and aminosalicylates can occasionally result in pancreatitis and pneumonitis. These responses are likely to recur; thus, the drug should not be resumed in these patients.

Discuss the safety of aminosalicylates in pregnancy?

Sulphasalazine is safe during pregnancy and nursing. There is less experience with the newer 5-ASA agents in pregnancy, however current evidence suggests that both topical and oral agents are safe in pregnancy