All patients
Hepatitis B (Full panel)	Hep BsAg (Infection – contraindication to treatment) Hep BsAb (?Immune) Hep BcAb (latent infection – seek advice if positive, may need prophylaxis)
Hepatitis C
HIV
Varicella	VZV IgG OR Documented history of vaccination (Patients who have been vaccinated do not necessary show positive IgG response, but still have protection)
Tuberculosis	Quantiferon assay Consider CXR in high risk individual
Consider
EBV, CMV, HSV
Syphilis
Strongyloidies
JCV

Vaccination

Consider Vaccination for:

Vaccination	Who to consider	Comments
Hepatitis B	At risk: - Family contacts, ATSI, migrant communities, IVDU, Prisoners, Health care workers/Police force, MSM,	Standard is 3 vaccinations – 0, 1 and 4 months Accelerated vaccination over 1 month can be considered – limited evidence and likely reduced efficacy.
Varicella	Test VZV serology or document vaccination history - If VZV negative and no documented history of vaccination - Older patients with positive VZV serology - >70yrs, however consider for patients >50 years if going on immunosuppression.	– Varicella vaccine – ideally 2 doses 1 month apart, however even one dose has reasonable efficacy. - Zostavax can be considered. Given as single dose. NOTE: Live vaccines – thus must be given at least 4 weeks prior to starting immunosuppression.
Influenza	All patients	Annual
Pneumococcal	>70 years (regardless of other risk factors) ATSI >50years Any patient with risk factors (previous pneumococcal infection, chronic disease, asplenia). Immunosuppressive medication is not listed as specific risk factor.	Single dose of 13PCV Dose of 13 PCV and later 23 PCV Dose of 13 PCV and later 23 PCV

Avoid Live vaccines:

• Immunosuppression should be delayed until 4-6 weeks after live vaccination

Live attenuated parenteral vaccines	Live attenuated oral vaccines
Viral	Bacterial	Viral	Bacterial
Japanese encephalitis (Imojev) Measles-mumps-rubella (MMR) Measles-mumps-rubella-varicella Varicella Yellow fever Zoster vaccine (Zostavax)	BCG	Oral rotavirus vaccine	Oral typhoid vaccine

Live attenuated parenteral vaccines

Live attenuated oral vaccines

Viral

Bacterial

Viral

Bacterial

Japanese encephalitis (Imojev)

Measles-mumps-rubella (MMR)
Measles-mumps-rubella-varicella
Varicella
Yellow fever
Zoster vaccine (Zostavax)

BCG

Oral rotavirus vaccine

Oral typhoid vaccine

Prophylaxis:

Bactrim in non-transplant setting

Steroid treatment

• Should be considered for patients on >/= 20mg/day for >1month

• This recommendation is far more important if co-existent risk factors exist:

o Malignancy

o Respiratory disease

o Co-administration of other immunosuppressant’s.

Other immunosuppression

• Azathioprine – consider if >3mg/kg/day

• Methotrexate – consider if >0.4mg/kg/week

In heavily immunosuppressed patients (e.g. post transplant)

• Bactrim

o Protects against – PCP, Toxoplasmosis, Isospora, norcardia, listeria and others

o Give for at least 3 months to lifelong

o Alternatives to bactrim include dapsone or atovaquone

• Anti herpes virus prophylaxis

o Usually valganciclovir

o Protects against CMV primarily (also HSV, VZV, EBV)

o By preventing viral infection-

- Reduces incidence of secondary fungal infections

- Reduces incidence of PTLD

- May reduce BOOP in lungs and vasculopathy in heart Tx

o 3-6 months often used

o Some units do not use routinely but monitor carefully and treat ASAP

• HBV prophylaxis

o If core positive but surface antigen negative then prophylaxis warranted

Calcineurin Inhibitors

· Bind to intracellular proteins and subsequently inhibit calcineurin

· This prevents (calcineurin from) activating transcription factor NFAT

· The primary effect of this is reduced production of IL-2

· Other cytokines down regulated:

o TNF-a, IL-3, IL-4, IFN-gamma

· Also reduces transcription factors NF-kB and AP-1

· Action primarily effects helper T-cells

· Does not have myelosupressive effect

· Reduces activation of immune system, has little effect once it is activated.

Cyclosporine

· Binds cyclophilin and the complex binds calcineurin and inhibits its effect on transcription

· Metabolised by CYP3A4

o Multiple drug interactions

Toxicity

· Nephrotoxicity

o Acute reversible

o Chronic irreversible

§ (Obliterative arteriolopathy – suggests endothelial damage)

· HTN

· Gingival hyperplasia (?can be Rx with metronidazole)

· Hirsutism

· Neurological – Tremor common (usually mild), encephalopathy and headache

· Induction of HUSTTP

· DM induction (and increased insulin requirements)

· Dyslipidaemia

· Increase K+, low Mg2+

· GI upset (common, 50%, but not limiting)

· Increased malignancies (more due to the immunosupression in general)

Tacrolimus

o Also binds calcineurin in a complex (with FKBP12)

o Similar efficacy to cyclosporine at std. doses

Toxicity

o Similar to cyclosporine:

o Nephrotoxicity

o HUSTTP

o Less likely to cause other cyclosporine SE (HTN, hyperlipidaemia, gingival hyperplasia, hirsuitism)

o More likely to induce DM

o Neurotoxicity more likely

o GI upset more common

mTOR inhibitors

Sirolimus and Everolimus

Use

· Transplant – heart and renal

· Treatment of Renal cell carcinoma

Interactions

· Metabolised via P-450

· Numerous interactions – caution when changing dose

· Interaction with cyclosporine

· Everolimus trough levels can be monitored

Toxicity

· Marrow suppression

o Anaemia (30-60%)

o Thrombocytopaenia

o Leukopenia

· Metabolic

o Hyperlipidaemia

§ TG and cholesterol elevated (via inhibition of LPL)

o DM – prolonged use can induce DM

· HUSTTP

o Has occurred in rare cases usually when cyclosporine co-administered.

· Renal function

o Minimal impact on its own, may be synergistic effect with cyclosporine

· Respiratory

o Associated with interstitial lung disease

· Impaired wound healing

Antiproliferative/Antimetabolic Agents

Azathioprine

Converted to 6-mercaptopurine
Then converted to different metabolites

6-TGN – induces immune cell apoptosis
Interferes with purine metabolism
Excess converted to toxic metabolite (6MMP)- responsible for hepatotoxicity
TPMT enzyme differences can determine effects

10% of population are slow metabolises
<1% have no enzyme and are at risk of severe toxicity – especially bone marrow toxicity

Toxicity/SE

• Myelosuppression (~27%)

o Leukocytopenia >thrombocytopenia>anaemia

• GI upset (mainly upper) – occurs in 25%

• Hepatitis (rare, usually mild elevation of LFTs in 5%)

• Pancreatitis

• Infection (particularly if leukocytopenia)

• Neoplasm/lymphoma

• Pregnancy – probably safe to use, some SE however NOT teratogenic

• Breastfeeding – probably safe

Interactions

• Allopurinol – blocks xanthine oxidase which metabolises azathioprine

o Must decrease dose by 25-33% or avoid combination

• Co-administration of ACE-I may increase risk of leukopenia

Dose:

• Start: 0.5-1.0mg/kg/day

• Increase over 3-4 weeks to target 2.0-2.5mg/kg/day

• Caution at extremes of body weight – may be better guided by blood testing.

• Lower dose if combination with allopurinol

• Lower dose if slow metaboliser (based on TPMT activity)

Monitoring

• FBC/LFT

o Every 2 weeks when starting (or changing dose) – continue for 6 weeks once stable dose reached.

o Then - Monthly for 3 months

o Then –3 monthly thereafter.

o If lymphocyte count <0.5 – consider dose reduction

o If total WCC <1.5 – consider withholding treatment

• MCV

o Dose related increase

o Roughly correlates with efficacy

o Not accurate enough to use as definitive marker of action – better used as marker of compliance.

• 6-TG and 6-MMP levels

o 6TG

- >400 correlates with myelosuppression

- 235-450 correlates with clinical efficacy

- <235 Poor efficacy

o 6MMP

- >5700 correlates with hepatotoxicity

o Check at:

- 4 weeks after starting or changing doses

- Then ~3 months after starting

- Then Annually

o Results:

- See table:

		6-MMP
		Low	High
6-TG	Low	Subtherapeutic dosing (or poor compliance)	Hypermethylation occurring Split or reduce dose and add allopurinol
6-TG	High	Supratherapeutic effect – reduce dose	Supratherapeutic effect – reduce dose

• Malignancy monitoring

• Advice to monitor for infections (and education regarding vaccination)

• Advice regarding pregnancy

Mycophenolate mofetil (MMF)

Metabolises to active agent – Mycophenolic acid (MPA)
Inhibitor of IMP dehydrogenase (IMPDH) – an important enzyme in guanine (purine) synthesis
Lymphocytes are dependent on de-novo synthesis while other cells use salvage pathway – hence selective effect.

Uses

· Transplantation

· SLE – renal crisis (as alternative to cyclophosphamide)

Pharmacokinetics

· Metabolised by glucuronidation, mainly excreted in urine

· Watch dose in renal failure

Toxicity

Leukopenia
GI upset – Diarrhoea, Vomiting, dyspepsia, nausea, abdominal cramping (75%)
?Increased risk of infections

CMV
May be protective against PCP

· Raised LFTs (25%)

· Pregnancy - Not safe, known teratogenic

Dose

· Mycophenolate mofetil 1-1.5g bd

· Mycophenolate sodium 720mg bd

· If GI side effects can try:

o Give with food

o Give tds or qid

o Switch to mycophenolate sodium

o Reduce dose

Monitoring

· FBC weekly for 1 month then:

· FBC every 2 weeks for 2 months then:

· FBC every 1-3 months ongoing

· Levels can be done but are complicated (see AMH)

Leflunomide (Arava)

Inhibits di-hydro orotate dehydrogenase (DHODH) resulting in inhibition of the pyrimidine rUMP
Inhibits

leukocytes adhesion, Memory T cells, Dendritic cells
NF-KB
Various other proposed mechanisms

May have anti-BK virus effect
No major modification needed for renal or hepatic dysfunction

Indications

· Rheumatoid arthritis – often in combination with MTX in patients who have failed monotherapy

· BK virus infection in renal transplant patients (experimental)

Adverse

o HTN

o GI upset

o Hepatotoxicity

~10%, usually reversible

o Myelosupression

Leukopenia is very rare

o Not safe in pregnancy

Methotrexate

DHFR inhibitor

This does not seem to account for its entire effect and alternative mechanism affecting adenosine signalling is also proposed

Pharmacokinetics

80-90% excreted unchanged in urine – therefore need to dose adjust in renal impairment
Oral, SC and IM dosing (later may be used due to variable bioavailability)

· Usually given weekly – minimises SE without effect on efficacy

· Concurrent folic acid – 1mg daily, may reduce SE and has not been demonstrated to reduce efficacy. Weekly folinic acid (leucovorin) may be similarly used.

· Drug interactions

o Caution using concurrent high dose bactrim (which also inhibits DHFR)

o Leflunomide increases risk of raised LFTs

Toxicity

· Depends on dose used (high doses used in chemotherapy)

Serious

· Hepatotoxicity

o Transaminitis in 10%, more severe disease rare

o AST level most predictive of damage

o Consider pause or cessation if > x2 ULN

o Consider reduced dose if ongoing mild elevation

· Pulmonary

o Many different types but hypersensitivity pneumonitis is most common

o Can occur at any dose

o Acute or chronic

o Restrictive RFTs on reduction

o Improve with cessation

o May be eosinophilia

· Myelosupression

o Neutropaenia

§ Dose dependent

§ Stop if count <1.0

o Lymphopaenia

§ Mild reduction common

§ Consider reduction if <0.8

o Pancytopaenia

§ Higher risk in elderly and renal impairment or using Bactrim

§ Cease MTX and start high dose folinic acid (15mg QID IV)

· Nephrotoxicity

o Precipitation of MTX crystals and tubular injury

· Pregnancy – absolute CI

o Cease for 12 weeks prior in male and female

· Malignancy

o Lymphoma and leukaemia risk is double, cautation unclear

o Probable increase in non-melanoma skin cancer

· Infection risk

o No general increase in risk

o Shingles risk is increased

o PJP rare case reports

Common

· GI upset

o Nausea and vomiting and less commonly diarrhoea

o Usually up to 72 hours post dose

o Try nocte dose or increase folic acid up to 5mg 6 days/week, or change to folinic acid 7.5mg 12 hours post dose

· Stomatitis and oral mucosal lesions

· Macular rash

· Alopecia

· CNS – headache, fatigue

o Often in 72 hours post dose

o Try reduction of dose by 5mg if severe

· Alopecia

· Fever

· Macrocytosis

Cyclophosphamide

· Alkylating agent

· Severe life or organ threatening disease

· Converted in liver to a variety of metabolites

· Excreted in urine – need to renal adjust

· Oral is more effective in many cases but has higher toxicity than IV

Toxicity

· Lymphopenia

o Almost universal with higher doses

o Concurrent steroids may worsen this

o Should reduce therapy if WCC < 3 to 4.

· Bladder toxicity

o Haemorrhagic Cystitis - Acrolein – is metabolite which is toxic to the bladder

§ Superhydration – fluid and frusemide to achieve UO >150ml/hr is effective

§ MESNA binds acrolein and can be given to reduce toxicity

§ Treatment is difficult - hydration, bladder washout, may need instillation of formalin or alum to stop bleeding, surgical options

o Bladder cancer risk is increased and yearly urine screening for haematuria is recommended.

o Cumulative dose and previous haemorrhagic cystitis are risk factors for TCC development

o It is thought that BK virus infection has a role in inducing toxicity

· Infertility

o Female

§ Relates to increased cumulative dose, oral dose and age (>25yrs), risk of complete ovarian failure in low risk groups 10-50%.

o Male

§ Risk less clear ?>50%

o Use of GnRH agonists to induce gonal quiescence may be of benefit

o Preservation of ovum and sperm

· Teratogenic

· Risk of infection increased – of multiple organisms

o PCP prophylaxis is recommended

o VZV reactivation

· Malignancy

o Increased risk of lymphoma

o Increased risk of bladder cancer

Biologics

TNF inhibitors
Infliximab
Entanercept
Adalimumab
Golimumab
Certolizumab

IL-1 Inhibition
Anakinra
IL-2 Inhibitors
Basiliximab (Simulect)
Daclizumab (Zenapax)
Alpha-4-Integrin AB
Natalizumab (Tysabri)

TNF inhibitors

Infliximab (Remicade)

Chimeric (human-mouse) IgG, TNF-a monoclonal antibody

Indications

RA
Ankylosing spondylitis
Psoriatic arthritis
Psoriasis
Crohn’s
UC

Entanercept (Enbrel)

recombinant soluble p75 TNF receptor :Fc fusion protein (also targets TNF-beta)
There are two naturally occurring TNF receptors – the ‘active’ one on cell surfaces and a soluble ‘decoy’ one produced to decrease TNF action.
This drug utilises the later, soluble TNF receptor in a more stable, long lasting form which clears the TNF.
Indications

RA
Anklyosing spondylitis
Psoriatic arthritis
Chronic plaque psoriasis

Adalimumab (Humira)

Recombinant humanised monocloncal TNF-a AB
Indications

Adult RA
Psoriatic arthritis

Golimumab (Simponi)

As per Adalimumab

Certolizumab pegol (Cimzia)

As per Adalimumab but pegylated

Adverse effects of TNF inhibitors

Infection

Opportunistic infections
Serious bacterial infections (high dose infliximab)
Reactivation of latent TB (infliximab >others)
Pneumococcus/influenza vaccine should be given before commencement

Administration

Injection site reactions
Infusion reactions
Hypersensitivity
Serum-sickness like reactions

Malignancy

Lymphoma (2-6x)
Controversial

Haematological

Pancytopenia, aplastic anaemia

Increased risk of CHF and mortality at high dose infliximab

Autoimmune

Human anti-chimeric antibodies to infliximab

i. Reduced incidence with MTX/AZA

ii. Abrogates use of infliximab if it occurs

Drug-induced lupus
Development of autoantibodies

Neurological

De novo demyelinating disease
Parkinsons disease

IL-1 Inhibition

Anakinra (Kineret)

Recombinant, IL-1Ra (competitive ihibitor of IL-1 binding IL-1R)
Indications

Active RA (combined with MTX but not TNF-Inhibitors)

IL-2 inhibition

Basiliximab (Simulect)
Daclizumab (Zenapax)
Antagonize IL-2R
Used for renal transplantation
Ongoing trials in other conditions

Anti-Alpha 4 Integrin Inhibitors

Natalizumab (Tysabri)
Inhibits T-cell entry into CNS
Used in MS

Anti-CD20 Antibodies

Rituximab

· RA - Proven useful in patients with rheumatoid arthritis

o Role of pathological antibodies/immune complexes in disease.

o Usually used in combination with methotrexate, NOT used in combination with anti-TNF therapy

· SLE – has been used successfully

Adverse effects

· Infusion reactions

o 30-45% at first infusion, ?due to release of cytokines from destroyed cells

o Hypotension, throat tightness, rash, nausea, back pain

o Premedication may help

· Infection

o Overall not increased relative to patients on methotrexate

o Maybe a small increase in Pneumocystis pneumonia

· PML - May be small increased risk

· Impaired vaccination response

· Human anti-chimeric antibody – up to 5%

o Decrease efficacy

o Increased risk of infusion reactions

Monitoring

From Practical Neurology

Summary of Side Effects

Cyclosporine	Nephrotoxicity HTN Gingival hyperplasia Hirsutism Neurological – Tremor common Induction of HUSTTP DM induction Dyslipidaemia Increase K+, low Mg2+ GI upset (common, 50%, but not limiting)
Tacrolimus	As for cyclosporine with the following exceptions: More DM More neurological SE More GI upset No gingival hyperplasia or hirsuitism
Azathioprine
Mycophenolate	Leukopenia GI - Diarrhoea, dyspepsia, nausea, abdominal cramping (75%) ?Increased risk of infections (May be protective against PCP) Raised LFTs (25%) Pregnancy - Not safe, known to be teratogenic
Sirolimus