IRISH DERM TUTOR

Methotrexate

Mechanism of action

Indications

Contraindications

Dosing

Information for patient

Screening investigations

Monitoring

When to stop

Side effects

Haematological

Gastrointestinal

Liver

Monitoring liver (PIIINP, US, Fibroscan)

Pulmonary

Carcinogenesis

Renal

Cutaneous

Overdose

Drug interactions

Vaccinations

Conception

Surgery

Prior cancer history

Intercurrent infection

Ciclosporin

Mechanism of action

Metabolism and excretion

Indications

Contraindications

Information for patient

Screening

Monitoring

Drug interactions

Phototherapy

Vaccinations

Adverse effects

Children

Pregnancy

Azathioprine

Acitretin

Different doctors/departments will have different ways of prescribing methotrexate

Some will be monitored purely by the dermatology department

But often monitoring can be performed in the community by the GP if there is a shared care protocol

Exact mechanism of action in in inflammatory dermatosis still subject to debate

Can be anti-inflammatory and immune modulating

Dihydrofolate reductase inhibitor, which blocks formation of tetrahydrofolic acid and interferes with purine and pyrimidine synthesis

• So get less nucleic acid synthesis in active T cells and keratinocytes:

Effects also possibly because it:

• Enhances adenosine release

• Lowers TNFa

• Inhibits JAK/STAT pathway

Absorption: oral bioavailability approx 70% (range 25-70%): explains why subcut route can be more effective

Metabolism: only small fraction metabolized

Eimination: mainly renal

Licensed:

Chronic plaque psoriasis

PASI 75 initially reported to be approx 70% (older studies) but about 40% in new trials (biologic comparison trials)

NICE consider methotrexate as the first line systemic agent for people with psoriasis under the following scenarios:

• It cannot be controlled with topical therapy

• It has significant impact n physical, psychological or social well being

and one or more of following apply:

1. Psoraisis is extensive (BSA > 10% or PASI > 10)

2. Localised but associated with significant functional impairment and/or high level of distress (eg severe nail disease, high impact sites - scalp, face, hands)

3. Phototherapy has been ineffective, can’t be used or has resulted in rapid relapse (defined as greater than 50% of baseline disease severity within 3 months)

Methotrexate can also be effective in psoriatic arthritis (except for spondylarthropathy)

Unlicensed:

• Inflammatory skin disease

◦ Atopic eczema

◦ Oral lichen planus

◦ Cutaneous sarcoid

• Autoimmune

◦ Scleroderma/SSc

◦ Lupus: DLE, SCLE, Chillblain lupus, lupus profundus

◦ Dermatomyositis

◦ Alopecia areata

• Bullous disorders

◦ Pemphigoid, pemphigus

• Others

◦ Hailey hailey

◦ Small vessel vasculitis

Absolute contraindications:

• Marrow dysfunction

• Dialysis/severe renal dysfunction

• Severe hepatic dysfunction/cirrhosis

• Women trying to conceive/pregnant/breastfeeding

• Certain immunodeficiency states

• Active TB/Hepatitis infection

• Pulmonary fibrosis/significantly reduced lung funciton

• Active peptic ulceration

• Concurrent trimethoprim therapy

• Hypersensitivity

Relative contraindications:

• Mild to moderate renal/liver impairment

• History of hepatitis B and C

• Gastritis

• Excessive alcohol intake

• Patient unreliability

• Recent live vaccination

• Male partners of women wishing to conceive

Oral or subcutaneous preparation used in dermatology

Always once weekly (important to get patient to take on same day every week)

2.5mg to 25mg dosing (prescribe 2.5mg tablets: so for instance if on 15mg patient will take 6 tablets of methotrexate once a week)

Typically start at low dose (eg 5mg) and build up over a number of weeks (typical maintenance 15mg per week

Folic acid decreases mucosal and GI side effects

• Folic acid 5mg can be taken once weekly a few days after the methotrexate dose (eg ‘Methotrexate Mondays, Folic acid Fridays’) or can even take it every day except the day having the methotrexate

Time to response: 6 weeks to 3 months

Counsel weekly dosing schedule

Written information about Methotrexate

Screen for drug interactions and advise patient about potential interactions with new medications (eg NSAIDs)

Advise re: alcohol intake, regular blood tests, increased risk of infection, need to avoid pregnancy

• FBC

• U&E

• LFT

• PIINP

• Hep B/C, HIV serology

• VZIG (if any doubt at all re: status)

• CXR (often done: to rule out any baseline disease. BJD guidelines: suggest if have disease that affects lungs)

• Quantiferon (only if high risk)

• Pregnancy test females of child bearing age

• FBC, U&E, LFT before dosing in week 2

• Then every 1-2 weeks for first month and until steady dosing regimen is achieved

• Once on stable dose perform every 2-3 months

• Folate if MCV increasing

• PIIINP at 3 monthly intervals

• Methotrexate polyglutamate (blood testing), an active metabolite of methotrexate, can be a useful adjunct to check compliance and need for dosage readjustment

When to consider stopping DMARD (NICE guidelines):

WCC < 3.5

Neutrophils < 1.6

Platelets < 140

Creatinine >30% from baseline over 12 months

AST/ALT > 100

Albumin drops stop MTX

MCV > 105: check TFT, B12, folate

Rash, mouth ulcers, N/V/D: stop

Acute SOB or dry cough: stop and get urgent opinion

Bruising or severe sore throat: check FBC

BJD guidelines (2016):

Withhold/decrease dose, consider discussion with haematogist if:

• WCC < 3

• Neutrophils < 1

• Platelets < 100

• MCV > 105 (check B12, folate, TFT)

AST/ALT increased by less than two times normal (repeat 2-4 weeks)

AST/ALT > than 2-3 times normal: withhold/decrease dose, consider risk factors and consider discussing with gastroenterologist

Acute SOB/dry cough: withhold/decrease dose MTX, repeat CXR and PFTs, discuss with respiratory team

Severe sore throat, abnormal bruising: withhold MTX; check FBC immediately

Mouth ulcer - try folic acid on every day other than MTX day. If severe, stop MTX

Nausea - try folic acid on every other day than MTX. Try anti-emetic or reduction in dose

Severe sore throat/abnormal bruising - stop and check urgent FBC

Unexplained acute dyspnoea or dry cough - stop and arrange CXR

MCV > 105: Think of other possible causes: check B12, folate, TFTs, medication interactions, alcohol

Serious infection/dehydration - stop MTX and restart once treated

Bone marrow suppression (can get anaemia, neutropaenia, thrombocytopaenia, pancytopaenia)

Patients need to look out for and report mouth ulcers, bleeding, bruising, fevers/infection

Can be abrupt

Can occur with dose increases

Severe myelosuppression rare but often in context of prescribing/dispensing errors, poor renal function or drug interaction (NSAID, anti-folates, anti-metabolites)

If have intercurrent illness that induces dehydration should omit MTX dosing until recovery

The first haematological test to become deranged in MTX-induced BM suppression are platelets as have shortest lifespan

Folic acid supplementation minimises risk

Methotrexate can sometimes unmask an underlying iron, B12, folate deficiency

If MCV > 105 do B12, folate, TFTs and monitor MCV

Anorexia

Peptic ulceration

Nausea and vomiting (dose related) in 25%- often settle with time

• Tends to occur within 12-24 hours of consumption (advice: take before bed or with food)

• Can increase folic acid dose to daily except day of MTX

• Consider ondansetron 8mg 2 hours before and 12-24 hours later

• Subcut MTX may reduce nausea

Diarrhoea

Ulcerative stomatitis

Mouth ulcers

Can cause a Hepatitis

Fibrosis with long term use

Biopsy can show evidence of hepatic injury but overall significance is unclear as most patient don’t progress to cirrhosis/clinically significant hepatic dysfunction

Patients with T2DM, alcohol abuse and obesity often have a degree of stiff, fatty liver at baseline already so need to keep this in mind

Practically, bear in mind that long-term MTX use is associated with increased risk of liver fibrosis, and this risk may be greater in those at risk of, or with pre-existing liver disease

Risk factors for methotrexate-induced liver fibrosis:

Alcohol

Obesity

DM

NAFLD

Increased lipids

Raised AST/ALT

History of liver disease

No folate supplement

Drugs

The routine use of liver biopsy for monitoring MTX hepatotoxicity is no longer recommended

LFTs in isolation inadequate for monitoring hepatic fibrosis development (good at detecting MTX-induced hepatitis)

Estimated that it occurs in 4% of patients with long-term use and it can develops despite normal LFT and ultrasound

There is evidence of increased risk of developing liver disease in psoriasis patients compared to PsA and RA patients on methotrexate

This may in part be related to the fact that they often have increased associated risk factors:

Procollagen 3 peptide assay monitoring for liver fibrosis:

Serum marker of collagen turnover

Do in psoraisis patients without PsA (as may be raised due to inflammation, also don’t monitor in paediatric patients or eczema patients)

Also raised in: smokers, cancer, bone remodelling (orthopaedic surgery, skeletal fractures, growing children, bone mets)

Do every 3 months

High negative predictive value with normal markers (90%+), low positive predictive value (approx 50%)

Refer for further specialist assessment if:

• 1 sample > 10mcg/L

• 2 consecutive samples > 8.0mcg/l

• 3 samples in 12 months > 4.2 mcg/l

Withdraw if:

• 3 samples in 12 months > 10mcg/l

Consider patient age and other treatment options despite abnormal P3NP before stopping MTX

Liver ultrasound:

• Unable to detect hepatic fibrosis until cirrhosis has developed

• May be useful for detecting steatosis and for assessing patients with abnormal LFTs

Fibroscan (transient elastogrpahy)

• Measures liver stiffness using modified ultrasound

• Technically difficult in obese patients

• Normal range is between 2-7 (kPa)

• Score of > 7kPa gives 85% probability of significant liver fibrosis

• Good at monitoring severe fibrosis but less predictable at mild or moderate fibrosis and may miss cases

Accuracy of fibroscan may be improved with combining its score with a serum biomarker of fibrosis

◦ Eg Fibrotest: A patented algorithm that calculates risk of hepatic fibrosis by looking at age, sex, ALT, Haptoglobin, apolipoprotein, bilirubin and y-glutamyl-transpeptidase (not validated in large cohorts of patients with PsO on MTX)

Alcohol and Methotrexate:

Risk of liver fibrosis is 2.5-5 times greater if more than 12.5 units per week

BJD guidelines (2016) recommend staying ‘well within maximum national limits’ (14 units per week)

Pragmatic discussion around occasional alcohol consumption possibly being allowed especially if have no hepatic risk factors, no DM and are not obese

Example: for psoriasis +/- PsA - a recommendation could be max 6 units per week

Could consider always doing baseline CXR to assess baseline disease prior to commencing MTX even if side effects are rare

Ask about smoking history and respiratory symptoms at baseline

Interstitial lung disease:

• A rare complication of MTX thereapy in rheumatoid arthritis (? patients more pre-disposed to it)

• Even rarer in patients with psorasis (pre-existing lung disease, PsA and smoking appear to be RF)

• Symptoms are non-specific and include dry cough and dyspnoea

TB:

• Link between MTX and TB reactivation not well defined

• Should ask about personal history of TB and of history of TB exposure

• Any suspicion of latent TB should result in screening for latent or active TB infection and treatment if positive prior to commencing MTX

Overall, risk of malignancy associated with low-dose MTX use in patients with psoriasis appears consistent with background population rates, but vigilance for lymphoma is advisable

Methotrexate may cause x3-4 fold increased risk NMSC and increased risk melanoma to lesser extent

May be association with lymphoma but is rare

Risk of myelosuppression is increased significantly in renal dysfunction

Methotrexate dosage dependent on eGFR:

• > 90: normal dose

• 20-50: Half dose

• <20: Avoid MTX

Risks of worsening renal function:

• Dehydration/Fever/Diarrhoea

• Certain drugs (eg NSAIDs)

If patients develop worsening renal function FBC should be monitored closely and dose reductions considered

Methotrexate-induced cutaneous necrosis:

Rare, risks include:

• Low use of folic acid

• Renal insufficiency

• Older patients

• Higher starting dose

Treat with folinic acid

Symptoms: mucositis, fever, diarrhoea, erythema, ulceration

Rarely cutaneous necrolysis

Use only 2.5mg tablet and make it very clear on the prescription the dose and frequency

If ≥ 1mg/kg of MTX ingested within hour:

• Give activated charcoal

• Admit to hospital

• Keep well hydrated

• Take serum MTX levels at least 4 hours after ingestion

• Give IV folinic acid 20mg with subsequent oral/IV dose followed by 15mg 6 hourly thereafter if MTX level unknown

◦ Use Toxbase for doses to be given when MTX level available

◦ Continue it till MTX levels < 0.05 or haematolgoical abnormaliteis have returned to normal and mucosal ulceration has healed

• Urine alkalinization with sodium bicarbonate may prevent MTX precipitation within renal tubules

• Human gCSF (eg filgastrim) can be used for toxic bone marrow suppression: 5mcgkg-1 daily to accelerate myeloid recovery

• Monitor and treat for sepsis accordingly

Detailed medication history essential

MTX initially bound to albumin so drugs displacing this (eg antibiotics) can increase MTX levels

MTX eliminated mainly in kidneys so drugs tat affect renal function can increase MTX levels

MTX hepatotoxic so caution with other hepatotoxic (alcohol, azathioprine, retinoids)

• NSAIDs

◦ Decreased elimination MTX

◦ Significant morbidity/mortality case reports but often in patients taking other drugs interacting with MTX (eg trimethoprim/allopurinol)

◦ Concomitant use of NSAIDs should be avoided but if co-prescription necessary do blood monitoring at least every 2 months

◦ Celecoxib does not interact with MTX

• Antibiotics

◦ Co-trimoxazole: bone marrow suppression

‣ Co-trimoxazole, trimethorpim, phenytoin and other antifolate drugs should be avoided in patients taking MTX

◦ Penicillins, tetracyclines, ciprofolxacin can increase MTX levels when high dose used but does not appear to be an issue in clinical practice

◦ If antibiotics given fore severe infection or infection not responding to standard treatment, MTX should be stopped until patient recovers and antibiotic course is complete

Avoid live-attenuated vaccines while on immunosuppression

Give at least 4 weeks prior to starting

MMR

Varicella

Oral polio

Typhoid

BCG

Yellow fever

If live vaccines need to be given for people on established immunosuppression it should be stopped for 6 months before vaccine is given

Inactivated vaccinations

• Annual flu vaccine (nb not new live vaccine offered to children)

• 5-yearly pneumococcal vaccine

• Safe to give during treatment - level of immunity achieved may be lower though

MTX is teratogenic and should not be used in those planning pregnancy or breast feeding

Women should not conceive while taking MTX for 3-6 months after last taking it

Males:

More controversial

There is a risk that methotrexate can damage sperm. This can affect the way a baby develops during pregnancy.

General advice (based on evidence from high dose MTX) : wait at least 3 months after last dose

Against:

• Low-dose methotrexate may induce oligospermia

• Animal studies suggest MTX induces damage to spermatogenesis (not examined in humans)

For:

• Observational studies between 42 and 139 men have found no increased risk of spontaneous abortion or foetal malformation

It is assumed when MTX is controlling an individual’s skin disease, it can be continued in perioperative period

But in patient’s who are due to undergo major surgery and have comorbidities such as DM which may alter infection risk, MTX may theoretically augment infection risk: the decision to continue should be made on a case by case basis

Advised that where patients are under active follow-up for cancer, the responsible team should be consulted and decision to start MTX should be discussed with them prior to commencing treatment

Low-dose MTX associated with increased risk of infection in particular:

• Pneumonia

• Skin/soft tissue infection

• UTIs

Similar rate of infection (7%) taking either MTX or Azathioprine for RA with most infections occuring within first 18 months

Stop MTX temporarily during severe infections or when infection is not responding to standard treatment

Can be re-started when infection has cleared

Opportunistic infections have also been reported: usually within first 12 weeks but risk remains throughout

Most reports in RA patients with concurrent medications

But rare reports in patients treated for psoriasis

Ciclosporin is a potent immunosuppressive agent

Calcineurin is a phosphatase activated by cyclophillin in the presence of calcium and calmodulin

In T cells calcineurin normally activates nuclear factor of activated T cells (NFATc) which promotes production of IL-2 and their cytokines that initiate activation and proliferation of T cells

Ciclosporin prevents activation of T-lymphocytes by:

• Binding to the cytoplasmic protein cyclophillin which inhibits activity of calcineurin

Other properties ciclosporin:

• Inhibits function of antigen presenting cells

• Inhibits release of mast cell mediators (eg histmaine, prostaglandins

• Inhibits keratinocyte proliferation and cytokine secretion

Different formulations exist which differ in bioavailability (eg Neoral and Capimune)

• Therepeutic index narrow - changes in efficacy and toxicity can occur if formulations swapped

Absoprtion varies between individuals (according to food intake, gut motility, plasma levels)

• Take on empty stomach

Half-life around 6 and a half hours

Metabolized by cytochrome P450 system (CYP3A4 and CYP3A5) in liver and has multiple potential drug interactions

Metabolites predominantly eliminated bile so alteration renal function does not increase blood levels significantly

Licensed UK:

Severe chronic plaque psoriasis

• Leads to an approximate PASI 75 of 70% at 12 weeks

• Also reported effective in erythrodermic psoriasis, generalised pustular psoriasis, palmoplantar pustulosis, acrodermatitis continua of hallopeau, psoriatic nail dystrophy

Severe atopic eczema

• Onset of benefit rapid (within days) and marked improvement usually within 2 months

Unlicensed indications include:

Palmo-plantar pustulosis

Chronic urticaria

PG

Behcet’s

Connective tissue diseases

Immunobullous disorders

LP

Nodular prurigo

No effect in :

Discoid lupus

Pemphigus vulgaris, pemphigus foilaceous

Most contraindications are relative rather than absolute but need extra caution with:

Impaired renal function

Uncontrolled hypertension

Severe hepatic dysfunction

Malignancy (systemic immunosuppression may promote growth if have prior or current malignancy)

Active infection

Concomitant UVB or PUVA

Immunodeficiency

Whenever possible short courses of treatment lasting up to 6 months are advised

Two divided doses per day

Ideal body weight should be used in obese patients for dose calculation

Psoriasis:

Non-urgent psoriasis cases:

• Commence 2.5-3mg/kg/day

• Increase if psoriasis not clearly improving after 1 month

Urgent cases:

• Can initiate at 5mg/kg/day

• Discontinue if sufficient response not achieved within 6 weeks on 5mg/kg/day

• Once sufficient improvement observed reduce by 0.5-1mg/kg/day to lowest effective dose

• Ideally limit to short courses lasting 3-6 months but not always possible (FDA guidelines: limit to 1 year of continuous therapy)

Eczema:

Recommended dosing range 2.5-5mg/kg/day

Licensed in eczema for 8 week courses

If starting dose of 2.5mg/kg does not achieve good initial response within 2 weeks dosage may be increased rapidly to maximum of 5mg/kg/day

If very severe - can start 5mg/kg/day

Can flare up rapidly on cessation so do gradual discontinuation regime (eg reduce daily dose/do alternate days dosing) and implement additional therapy

Don’t seem to be at increased risk of bacterial cutaneous infection - treat with appropriate antibacterials (be wary of interactions; eg erythromycin)

Herpes: treat prior to commencing. If get herpes don’t necessarily need to stop unless severe

Use of longer term ciclosporin in adults with eczema (ie up to 12 months) has been studied and shown to be genereally safe and effective

Strategies to minimize risk associated with ciclosporin:

Intermittent short-course therapy

Rotational therapy with other modalities

Short term use for management of acute severe disease

Provide PIL

Advise against pregnancy if possible

Make patient aware of potential for hazardous interactions with other drugs and need to warn healthcare professionals about concurrent medications

History and exam (exclude infection and malignancy)

Encourage adults to comply with national cancer screening programmes

Comprehensive medication check

Blood pressure (ideally on 2 occasions 2 weeks apart)

Urinalysis

Pregnancy test if appropriate

Bloods:

FBC

U&E (Ideally 2 weeks apart: at least two/prefarably 3 measurements: mean value recorded as baseline)

LFT

Uric acid

Lipid profile

Hep B/C serology

HIV

VZIG (if any doubt on status)

+/- Quantiferon (if high risk for TB)

+/- CXR (if high risk for TB)

U&E and blood pressure fortnightly for 2 months, then monthly, then when stable on long-term treatment after 4 months monitor every 2-3 months

• Increase frequency if rise in BP or creatinine

LFT, Lipids, Magnesium, Uric acid can be monitored at less frequent intervals depending on results

Serum creatinine:

If rising more than 30% above baseline then repeat within a fortnight

• If sustained reduce by at least 1mg/kg/day for at least one month

• If value falls back to less than 30% above baseline continue at this dose

• If value does not fall to less than 30% above baseline discontinue ciclosporin

• Can try reintroduction of ciclosporin when renal funciton within 10% of baseline but if recurs back to > 30% then discontinue permanently

If using ciclosporin >2 years you get more renal fibrosis and this may not be detected with creatinine measurements (can do isotope GFR every 2 years)

Blood pressure:

NICE guidance: aim for target below 140/90 (130/80 if have DM with complications)

Persistent elevation managed by reducing dose or using antihypertensive agent

Ciclosporin level:

Do only if investigating compliance, concerned about drug interactions or have unexpected deterioration in renal function

Long, long list of drugs that interact with ciclosporin so always do comprehensive check

Nephrotoxic drugs:

• NSAIDs, Aminoglycosides, Quinolones, Amphotericin B increase risk of nephrotoxicity

• Diclofenac levels increased when given with ciclosporin so need to half diclofenac dose

• ACEi and potassium-sparing diuretics increase risk of hyperkalaemia

Statins: increased risk muscular toxicity (weakness, pain, myositis, rhabdomyolysis) - pravastatin not metabolised by CYP450 so if need to use this

Digoxin: risk of digoxin toxicity

Methotrexate: reduce elimination of each other

Aciclovir: increase risk of nephrotoxicity

Anti-malarials: increase concentration of ciclosporin

CYP450 inducers and inhibitors:

Ciclosporin is metabolised by the hepatic CYP450 system leading to number of potential drug interactions to change ciclosporin levels

Think CRAP GPS use SICKFACES.COM (sorry GPs!!!)

Inducers:

‘To induce you reduce’ ciclosporin levels: CRAP GPS

• Carbamazepine

• Rifampicin

• Alcohol

• Phenytoin

• Griseofulvin

• Phenobarbitone

• Suphonylureas

Also: St. John’s wort

Inhibitors:

Inhibitors increase ciclosporin level

• Sodium Valproate

• Isoniazid

• Cimetidine

• Ketoconazole

• Fluconazole/Itracconaole

• Alcohol and grapefruit juice (avoid graprefruit juice)

• Chloramphenicol

• Erythromycin

• Sulfonamides

• Ciprofloxacin

• Omeprazole

• Metronidazole

Patients who received prior PUVA appear to be high risk of developing SCC when subsequently immunosuppressed

Phototherapy should be avoided in combination with ciclosporin

Use of ciclosporin should be regarded as relatively contraindicated with ‘substantial’ prior exposure to phototherapy

Influenza annually

Pneumococcal every 5 years

GI:

• Nausea, vomiting, reduced appetite, diarrhoea, weight loss

Hypertension:

• If SBP above 140 or DBP above 90 recheck in 2 weeks

• If remains elevated reduce by 25-50% or treat with antihypertensive (nifedipine can be useful as has nephroprotective effect but can cause gingival hyperplasia)

Nephrotoxicity:

• Effects are related to dose and duration of treatment so intermittent short courses preferable

Metabolic:

• Hyperkalaemia, hypercalciuria, hypomagesaemia (muscle cramps), hyperuricaemia

Malignancy:

• NMSC (especially SCC) – significantly increased in those exposed to PUVA

• Some studies report increased incidence lymphoma

Gingival hyperplasia:

• Worsened by poor oral hygiene

Neurological:

• Paraesthesia or tremor, seizure threshold may be lowered

Hepatotoxicity:

• Uncommon at lower doses used in psoriasis but any liver disorder should prompt dose reduction/discontinuation

Hypertrichosis

Hypercholesterolaemia

Increased risk of infection (including opportunistic infection)

Probable small increased risk of cancer associated with long term therapy

Headaches

Generally well tolerated in children

Can be used off license in children aged 2 years and older

Naturally avoid in pregnancy where if possible but does not appear to be teratogenic (evidence from transplant patients)

Some reports of an association with premature labour

Manufacture: ‘avoid in pregnancy unless benefits to mother justify potential risks to foetus’

FDA category C

Has been reported to be effective in generalized pustular psoraisis of pregnancy

Ciclosporin is excreted in breast milk and mothers taking drug should not breast feed

Synthetic purine analogue

It is a prodrug

After oral ingestion and absorption it is rapidly hydrolysed to and imidazole derivate and (methylnitroimidazole) and 6-mercaptopurine (6-MP)

6-MP is metabolised by competing enzymatic pathways to form various active and inactive metabolites

The thioguanine nucleotides are the active metabolites

Thioguanine nucleotides are incorporated into DNA and have antiproliferative effects especially on lymphocytes and other haematopoetic cells

The principal deactivating pathways are regulated by the enzymes thiopurine methyltransferase (TPMT) and xanthine oxidase (XO)

Inherent low enzyme activity or drug intereactions can lead to impairment of these pathways and can lead to the accumulation of thioguanine nucloetides which can be toxic and cause risk of life-threatening bone marrow suppression

TMPT activity is often measured prior to commencing Azathioprine to help prevent this occurring

UK licensed indications for AZA:

Pemphigus vulgaris

SLE

Dermatomyositis/polymyositis

Other uses:
Atopic dermatitis

Chronic actinic dermatitis

Bullous pemphigoid (similar efficacy to MMF)

Vasculitis (Behcet’s, HSP, severe cutaneous LCV, granulomatosis with polyangiitis

Smaller studies:

PG

Lichen planus

Erythema multiforme

PRP

Hypersensitivity to Azathioprine or 6-MP

Very low/absent TPMT levels

Severe infection

Pancreatitis

Severely impaired hepatic function or bone marrow depression

Live vaccines

Pregnancy

Lactation (excreted in breast milk)

Malignancy (due to possible increased risk of disease progression)

Special circumstances:
HIV not a contraindication but patients should be stabilized on HAART

All patients who are seropositive for HBV and HCV should be discussed with a hepatologist or infectious disease specialist as prophylactic antiviral therapy may be required

Available in 25mg and 50mg tablets

Can ge given once or twice daily, take with food

Onset of action is slow, effects may take several months

Dosing usually 1-3mg/kg (titrate according to response and side effects)

Usual starting dose is 0.5-1mg/kg for 4 weeks proving TPMT (enzyme that metabolizes azathioprine) levels are satisfactory - minimizes risk of nausea

Dose can then be increased according to baseline TPMT and FBC

Maintenance dose should be based on TPMT activity

In general if there is absent TPMT activity it is contraindicated except in exceptional circumstances where greatly reduced dose (5-10% of usual) with close haematological and metabolite monitoring is essential

Reduced TPMT activity results in greater risk of myelosuppression/pancytopaenia and other side effects: may need to lower starting dose

Diuretics, some NSAIDs and sulfasalazine may have inhibitory effects on TPMT but clinical relevance of this is unclear

TPMT unreliable 60 days after blood transfusion

With normal or high activity one such regime could be 2mg/kg/day for 1/12, then 2.5mg/kg/day and adjust dose within these limits depending on s/e’s and response
If there is no response at 3 months stop the medication

Full skin exam (? Evidence of skin cancer)

Pregnancy test females

Bloods:

• FBC

• U&E

• LFT (GGT)

• Hep B/C serology

• HIV test

• VZIG

• Quantiferon

• TPMT

CXR

Counselling:

Explain onset of action is slow and benefit may not appear till after 2-3 months

Advise pnuemococcal and annual influenza vaccines (ideally at least 2 weeks prior to starting)

Advise re: cervical smears/mammograms

Advise re: risk of skin cancer with prolonged use (also advise of lower potential risk of lymphoma)

Advise patients to use high factor sun block and need for excellent sun protection behaviour

Advise of potential risks of pregnancy where appropriate

Ensure that patients clearly understand the need for regular blood monitoring in order to minmise the risk of adverse effects

Advise of increased risk of infection

Advise to seek urgent medical attention if notice any of the following:

High fever/severe flu-like illness (also if associated with rash)

Severe sore throat

Unexplained bruising/bleeding

Jaundice

Monitoring:

Weekly FBCs for 4-8 weeks, then monthly or no less than 3 monthly

Keep a particular eye out for low neutrophils as an early decrease that still has normal total WBC range may herald a more severe neutropaenia

U&E, LFT every 1-2 weeks during first few months as hepatotoxicity is seen during this period

Once stable every 3 months

Not routine to measure thioguanine nucleotides but can consider only to assess adherence and occasionally to guide dose adjustments

Drug interactions:

Allopurinol and febuxostat inhibit xanthine oxidase leading to increased active metabolites (6-thioguanine nucleotides) with potential life threatening myelotoxicity if given with azathioprine

ACEi may increase risk of anaemia or leucopaenia in those with renal impairment

Warfarin - reduced efficacy of warfarin (need caeful monitoring and dose increase)

Ribavirin - inhibits an enzyme in the purine salvage pathway and can cause severe pancytopaenia with azathioprine

Other immunosuppressants: MTX, cyclophosphamide, ciclosporin

Drugs which cause unintended myelotoxicity: trimethoprim, cotrimoxoazole, sulphamethoxazole, sulfasaliszine, clozapine

Side effects:

Gastrointestinal:

N/V, reduced appetite, abdominal pain, diarrhoea, weight loss

Common and self-limiting - minmised by gradual dose esalation, divided daily dose and taking after food

Hepatotoxcitiy:

Mild derangement transaminases (< 2 times upper limit of normal) common often settles with continued treatment and may not require dose adjustment

Deteriorating or sustained elevations require dose reduction or discontinuation

Acute drug induced liver injury can be hepatocellular or cholestatic

Cholestatic injury may take longer to resolve

A chronic pattern of liver injury termed nodular regenerative hyperplasia has been reported in IBD and transplant patients

Haematological:

Get bone marrow suppression

Can be fatal

Baseline TPMT measurement does not identify all patients at risk

Leucopaenia is the commonest but can also get anaemia, thrombocytopaenia, and risk of potentially fatal agranulocytosis

Can develop suddenly or develop slowly over months

Mild lymphopaenia (0.5-1) is often observed and does not usually lead to complications

No specific guidelines for dose reduction on haematological indices, one regime could be:

Decrease dose by 50% and closely monitor if:

• Have mild reduction in Hb

• Leucocyte count 3-4

• Platelets 70-100

• Original dose can then be resumed if values normalised

• If values continue to trend down then stop the medication

Macrocytosis is also common and can be used to monitor compliance (B12 and folate deficiencies should be ruled out)

Drug hypersensitiviy syndrome:

Is idiosyncratic and immunologically mediated

Potentially fatal if have multi-organ involvement

Is uncommon but usually starts within the first few weeks of treatment

Often get non-specific symptoms like a flu-like illness (nausea, malaise, arthralgia) with a rash (urticarial, maculopapular, vasculitic)

In severe cases can get hypotension and shock

Treatment should be stopped immediately if suspected

Malignancy:

Increased risk of photo-carcinogenesis and non-melanoma skin cancer

The absorption spectrum of 6-MP peaks at 340nm (within UVA). 6-MP is incorporated into DNA and when it is irradiated and free radicals are generated causing DNA damage

So patients get increased UVA sensitivity and increased carcinogenesis

Transplant patients: Azathioprine combined with other immunosuppressant (200-fold increased risk of NMSC)

Need to advise patients about sun protection, self exam and the need to report any suspicious lesions

Azathioprine has been associated with lymphoma in transplant patients and IBD patients but may be due to intensity of immunosuppression or the underlying bowel disease

It is less clear if patients on azathioprine for dermatology have an increased risk of internal malignancy

Advise that there is no obvious risk for treatment periods less than 1 year and if they require it for longer it appears to be small

Infection:

May increase risk of infection even in absence of neutropaenia but does not appear to be a common clinical problem among dermatology patients

May be more susceptible to severe infection with VZV

Non-immune individuals may require VZ immunoglobulin or prophylactic aciclovir if they have significant exposure to chicken pox or herpes zoster

Other reports:

Pancreatitis in IBD patients

Acute or interstitial pneumonitis

FDA category D: benefit may outweigh risk if IF life-threatening or severe disease

• Increased risk of low birth weight and prematurity in those exposed to azathioprinein preganncy

• Increased risk of spontaneous abortion

• Male fertility not afffected

Special considerations:

Pregnancy and conception:

• No conclusive evidence that it is teratogenic but it does cross the placenta

• Increased risk of low birth weight and prematurity in those exposed to azathioprine in preganncy

• Increased risk of spontaneous abortion

• FDA category D: ‘Evidence of foetal risk which may be outweighed by maternal benefits in life-threatening or severe disease’

• Male fertility and sperm quality is not affected

Lactation:

• Negligible amount present in breast milk

• Controversial as WHO advised that the risks to the infant outweigh any benefit but recent evidence does not support this

  
  
  

Children:

• Licensed for use in childhood and reported to be safe and effective for severe atopic eczema

• High doses may be needed to achieve remission (2.5-3.5mg/kg)

• Long-term use needs careful consideration due to riks of skin cancer increasing with duration of usage

• Photo-protection obviously essential

  
  

Elderly:

• Be aware of drug interactions

• More susceptible to adverse effects so lower doses advised
  
  
  

Mechanism of action:

Retinoid -derived from vitamin A

Metabolite of eteretinate

• Anti-proliferative and anti-inflammatory properties

• Reduces keratinocyte proliferation and normalises differentiation and cornification

• Inhibits vascular endothelial growth factor and inhibits intraepidermal neutrophil migration

• Inhibits IL 6 driven induction of TH 17 cells which plays pivotal role in psoriasis

Indications:

Licensed:

Severe psoriasis that cannot be managed by topicals or phototherapy

Palmoplantar pustular psoriasis

Severe Darier’s

Severe congenital ichthyosis

Unlicensed indications:

Erythrodermic psoriasis

Pustular psoriasis

Severe hand eczema

Severe Dariers

PRP (can be considered first line)

Severe congenital ichthyosis

Lichen planus

Discoid lupus (similar efficacy to antimalarials)

Prophylaxis of NMSC in organ transplant patients

Is a good option in hyperkeratotic psoriasis and pustular psoriasis

Can use acitretin in combination with phototherapy:

Can get better response

Can use lower doses of acitretin and phototherapy

Can be used with UVB or PUVA

Contraindications/cautions:

Pregnancy

• Highly teratogenic

• Long half life, increased if combined with alcohol (as convereted to eteretinate)

• Avoid in women of childbearing potential

• If giving in women of childbearing potential have to be on pregnancy prevention programme and use effective contraception for 4 weeks before to 3 years after stopping acitretin

• Acitretin reduces the efficacy of the progesterone only pill so if on this may need to switch to combined OCP

• Ideally start on 2nd/3rd day of menstrual cycle

Hyperlipidaemia

Should not donate blood on and for 3 years after stopping

Caution in liver dysfunction and alcohol dependency

Eliminated reduced with severe renal dysfunction

Dosing:

Start 25-30mg daily (or 0.5mg/kg)

Adjust dose after 2-4 weeks according to response and side effects

• Maintenance 25-50mg od po (with careful titration up)

• Max dose 75 mg daily

Initial flare may occur

Improvement usually evident by 4 weeks

3 months to see optimal response

Taking it with fatty meal or milk increases its absorption

Consider lower starting dose in erythrodermic psoraisis

Consider lower dosing in Darier’s (eg start at 10mg daily, maintenance 10-25mg)

Similar low doses can be used in combination with phototherapy

Screening investigations:

FBC

U&E

LFT

Lipids

Glucose

Pregnancy testing if relevant

Monitoring:

Lipids and LFT monthly for 2 months

Then 3-6 monthly

Monitor for symptoms of development of hyperostosis +/- skeletal X-ray

Growth charts for those under 18yo (risk of premature epiphyseal closure)

SE:

Mucocutaneous:

• Dry lips, eyes, nostrils, skin

• Scaling and erythema particularly affects face and palmoplantar (peeling) skin

• Chelitis

• Conjunctivitis, Keratitis

• Nose bleeds

• Prescribe emollients, lip balms, eye drops and lubricants as necessary

• Increased skin fragility

• Photosensitivity

Hair loss

• Dose dependent.

• Occurs in up to 75% of patients but only minority severely affected

• Usually reversible within 6 months of discontinuation

Ocular

• Dry eyes

• Reduced night vision rarely reported

Hyperlipidaemia

• Especially if have other risk factors (eg alcohol, DM, obesity, family history)

• Dose related

Hepatitis

• Transient modest rise in transaminases common

• Acute hepatitis and jaundice are rare

• Discontinue if 2-3 x above upper limit normal

Neurological

• Headaches

• Benign intracranial hypertension rarely reported

Musculoskeletal

• Myalgia, arthralgia

• DISH

Psoriasis flare

Brittle nails/parnonychia

GI upset

Increased risk of skin infection

Mood changes: include depression/anxiety

Diffuse idiopathic skeletal hyperostosis (DISH)

Long term (> 2 years) treatment associated with increased risk of DISH-like changes of the spine and calcification of extraspinal tendons and ligaments, especially:

• Ankles

• Pelvis

• Knees

Routine X rays not indicated in asymptomatic patients

Do targeted radiography for atypical MSK pain

Drug interactions

Tetracyclines (risk of intracranial hypertension)

Vitamin A

Alcohol (increased hepatotoxicity)