IRISH DERM TUTOR

The first video covers from the introduction to severity assessment - the times to the relevant sections are noted in the headings

Introduction - epidemiology (01:30), causes (02.25), exacerbating factors (03.45), pathogenesis (06.15)

Subtypes: (07.44)

Chronic plaque psoriasis (07.50)

Guttate psoriasis (10.15)

Pustular psoriasis (11.15)

Palmoplantar pustulosis (16.20)

Acrodermatitis of hallopeau (17.35)

Erythrodermic psoriasis (18.15)

Histopathology (19.10)

Psoriasis associations (20:15)

Nail psoriasis (22.20)

Psoriatic arthritis (24:20)

Severity assessment (26:00)

Treatment

Topical treatment

Phototherapy

Systemic treatment (and NICE guidance)

Biologics

Anti-TNFa agents

Adalimumab

Certolizumab

Etanercept/Infliximab

Anti IL-12/23

Ustekinumab

Anti IL-17

Secukinumab

Ixekizumab

Brodalumab

Anti IL-17 agents considerations

Anti IL-23

Guselkumab

Risankizumab

Tildrakizumab

Psoriatic arthritis extra

Psoriasis is a chronic inflammatory skin condition and one of the commonest conditions we see in dermatology

Epidemiology:

Affects 2-3% population in Europe

Affects men and women equally but men more likely to have severe disease

Tends to persist lifelong, fluctuating in extent and severity

About 1/3 of patients with psoriasis have family members with psoriasis

Age at onset:

Bimodal

Early onset < 30 years (Peak 16-22)

• 75%

• HLA-Cw6 association

• More likely to have familly history

• More likely to be severe, unstable disease

Late onset > 40 years (Peak 55-60)

• Sporadic and not HLA associated

What casuses psoriasis:

Genetics, environmental factors and the immune system all play a role in the pathogenesis of psoraisis

Genetics:

Studies have reported 72% concordance in monozygotic twins and 23% in dizygotic twins

More recently genome wide association analysis has mapped at least 80 loci that can be associated with psoriasis

The major psoraisis susceptibility locus is termed PSORS1 and lies within the major histocompatibility complex (MHC) on chromosome 6

Within this locus, HLA-C*06:02 is the genetic variant that makes the largest contribution to psoriasis susceptibility

Inheritance of one allele of HLA-C*6:02: increases risk of psoriasis 4-5 times

Environmental factors:

Infection:

Streptococcal infection can cause a flare of psoriasis (eg guttate psoriasis)

Interestingly get a similar T cell repertoire in infected tonsils as is found in the skin in psoriasis

Medications:

• Steroids (it is important to be aware of the risk of a flare or development of pustular psoriasis on withdrawal of steroids)

• Lithium, beta blockers, systemic anti-malarials, intereron-alpha

• TNFa inhibitors: can get paradoxical psoriasis affecting palmoplantar areas and scalp (this is a class effect so if get with one TNFa inhibitor likely to get with another)

Smoking:

The Rate of smoking is increased in psoriasis patients compared to normal population

Palmoplantar pustulosis is almost exclusively seen in smokers but it is still unclear if smoking cessation helps improve it once it has developed

Psychological distress:

Up to 80% report worsening of psoriasis in relation to psychological stress

Endocrine factors:

Pregnancy (although psoriasis often improves during pregnancy thankfully)

Hypocalcaemia

Physical trauma:

Koebnerisation (appearance of skin lesions of a pre-existing dermatosis on areas of cutaneous injury)

(other causes of koebner phenomenon - lichen planus, vitiligo, molluscum contagiosum, bullous pemphigoid)

Role of immune system:

Psoriasis is a T-cell mediated disorder primarily driven by pathogenic T cells

It involves prominent involvement of helper T-cells and their secreted cytokines

Increased levels of T helper 1(Th1) and Th helper 17 (Th17) subsets and each subset secretes their own ‘signature’ cytokines

The cytokines TNFa, IL 12, IL 23 and IL 17 all contribute to the disease and as such are the targets of the different biologic treatments

The T cells interact with dendritic cells, keratinocytes and neutrophils under the influence of various cytokines and this process leads to keratinocyte proliferation, neutrophil chemotaxis and angiogenesis which leads to a psoriatic plaque

Of note, Keratinocytes tend to move from basal layer to upper layer in 3-5 days (compared to normal of 28 days)

Click here to skip to discussion about biologics and cytokines pathway which is discussed in greater detail

Symmetric distribution of demarcated plaques

‘Salmon pink in colour with silvery scale’

Common sites:

Scalp

Extensors elbows and knees

Sacrum

Hands and feet

Other areas to look for as a clue it may be psoriasis: behind the ears, the nape of the neck, the umbilicus

Ranges from mild to very extensive

Scalp psoriasis: can be difficult to treat and can have significant affect on quality of life

Flexural psoriasis:

The moist occlusive surfaces prevent build up of scale - appears red, macerated and shiny

Often get overgrowth of candida (see satellite lesions) so  often use combination medication such as trimovate (moderate steroid, antibacterial, antifungal) or lotriderm (potent steroid, antifungal - for very short period as have much higher risk of steroid side effect in these areas)

Genital psoriasis:

Is very important to ask about as it can cause issues with sexual function and can be very difficult to treat

Patients often reluctant to disclose it is an issue

Widespread small plaques

Gutta is latin for ‘rain drop’

Commonly seen in children following a streptococcal infection (look for elevated ASOT)

Generally is self resolving over 3 months

40% of patients with guttate psoriasis will go on to form chronic plaque psoriasis

Can be generalised or localised

Generalised:

• Acute generalised (pustular psoriasis of von zumbusch)

• Subacute annular and circinate pustular psoriasis (like plaque psoriasis but with pustules within the plaques- patients usually are well)

• Acute generalised pustular psoriasis of pregnancy

Localised:

• Palmoplantar pustulosis

• Acrodermatitis of hallopeau

Acute generalised pustular psoriasis

2 main groups:

1. Arising in chronic plaque psoraisis patients with triggering factors:

• Pregnancy

• Sudden withdrawal of steroids

• Other medications (beta blockers, aspirin, anti-inflammatories)

• Infection

• Hypocalcaemia

2. Generalised pustular psoriasis arising de novo:

• May be the only manifestation of psoraisis

Recent research suggests that generalised pustular psoriasis and palmoplantar pustulosis are actually distinct from classical psoriasis with a different pattern of immune activation:

• Generalised pustular psoriasis alone can be associated with IL 36 receptor antagonist mutations

• Generalised pustular psoraisis in patients with preceding chronic plaque psoriasis can be associated with CARD14 mutations

Clinical presentation of acute generalised pustular psoriasis:

Often precipitated by burning sensation, dryness and tender skin

Develop ‘lakes’ and plaques of pustules

Can lead to erythroderma

As pustules dry you get exfoliation

Nails often involved

It is a dermatological emergency - patient scan be unwell with systemic inflammatory response syndrome (SIRS), can get:

• Electrolyte abnormalities, dehydration and tachycardia

• Fevers

• Elevated inflammatory markers

Management of acute generalised pustular psoriasis:

Admit patient

Screen for infection!!!

(Can sometimes be difficult to tell if patient is septic or if it is simply a severe SIRS response)

Regular emollients (emollin spray is a good option)

Some don’t use topical steroids in case it exacerbates a flare when stop them but some cases a moderate topical steroid may be used

Non-adhesive dressings

Analgesia

Hydration

Monitor bloods

In some cases could consider ciclosporin but it can be hard to tell sometimes if there is an underlying infection driving the pustular psoraisis so can be a tough judgement call

Pustuolosis of palms and soles

Almost exclusively seen in smokers

Sterile pustules remain localized to palmoplantar surfaces

Pustules are very superficial and dry out leaving brown adherent scale which peels off

Patients often report a sensation of it feeling like walking on glass

Disease runs a chronic course

Often don’t have any psoriasis elsewhere

Sterile pustules starting at tips of fingers/toes and that spread proximally

Nail can become severely dystrophic and can lose the nail

Terminal digit may atrophy (acral osteolysis)

Can be very difficult to treat

Options: ciclosporin (but generally don’t want to be on for long time), acitretin, some reports showing efficacy with apremilast

> 80% Body surface area affected

Problems with temperature reguation, fluid loss

(superficially to deep)

Neutrophils in stratum corneum

Parakeratosis

Loss of granular layer

Psoriasiform hyperplasia of epidermis

Thinning of suprapapillary plates

Capillary dilatation and oedema in dermal papillae

Superficial perivascular lymphocytic infiltrate

Neutrophil collections:

Munro microabscesses: collection of neutrophils within the stratum corneum

Spongiform pustule of Kogoj: subcorneal collection of neutrophils

Think of psoriasis as a systemic inflammatory disease with multiple associations so need to consider these during consultations

• Psoriatic arthritis

• Nail psoriasis

• Metabolic syndrome

  • Hypertenison

  • Dyslipiadaemia

  • Insulin resistant DM

  • Obesity

  • Higher CVD risk

• Psychosocial:

  • Reactive depression

  • UK GP database: psoriasis patients more likely to have diagnosis of depression (HR 1.39 CI 1.37-1.41)

  • Approx 20% patients require treatment with antidepressants

  • Higher rates of suicidal ideation

• Alcohol:

  • Excess alcohol/alcohol misuse reported in 1/3 of patients with moderate-severe psoriasis

  • Associated with more severe disease

  • Important to screen for

• Inflammatory bowel disease

• Ocular inflammation (iritis, uveitis, episcleritis) 

Present in apporx 45% of patients with psoriasis

80% of patients with psoriatic arthritis have nail psoriasis

If nail matrix affected can get pitting (eg if focal part matrix affected), ridging and nail dysrophy (eg if all matrix affected)

If nail bed affected get nail lifted off the bed - oil drops, subungual hyperkeratosis, distal onycholysis

Can see splinter haemorrhages also

Topical preparations don’t penetrate nail bed or nail matrix making treatment very difficult

15-30% of patients with cutaneous psoriasis

Can occur prior to skin involvement but majority of the time occurs after skin invovlement

Presentations:

DRAMA

DIP joint predominant disease

Rheumatoid arthirits like presentation

Asymmetric oligoarthritis

arthritis Mutilans (grossly deformed hands and/or feet - seen less frequently now due to better treatments)

Ankylosing spondylitis like arhritis

For more info on psoriatic arthritis see end of notes or click here

Different severity scores can be used to measure how clinically severe the psoriasis is, how it affects a patient’s quality of life and to screen for psoriatic arthritis

These scores are sometimes used when assessing whether a patient is a candidate for a systemic agent

PASI -

Measures the severity and extent of psoraisis

Based on body surface area affected and the degree of erythema, induration and scaling in different parts of the body

You can download a pasi calculator app on your phone or simply look it up online - here is a link to the calculator I use:

Psoriasis Area Severity Index (PASI) Calculator (corti.li)

DLQI -

A questionnaire for a variety of skin diseases (not specific to psoriasis)

Measures the impact that a skin disease has a patient’s quality of life

Scored out of 30 and asks how the skin disease has impacted the patient over the last 7 days

Again a simple google will bring this questionnaire up (although it is usually quite easy to find one in a dermatology clinic)

PEST score -

A screening tool for psoriatic arthritis

Patient with psoriasis who do not have a diagnosis of PsA should ideally complete an annual PEST score

A score of 3 or more indicates consideration of rheumatology referral

The questionnaire asks patients to tick the joints that are affected on an image and asks the following questions:

1. Have you ever had a swollen joint (or joints)?

2. Has a doctor ever told you that you have arthritis?

3. Do your finger nails or toenails have holes or pits?

4. Have you had pain in your heel?

5. Have you a finger or toe that was completely swollen and painful for no apparent reason?

Emollients:

Encourage regular use of emollients - greasy ointment preparations tend to be better

(see eczema section or click link here for further info on emollients)

Vitamin D analogues:

Effective and safe in psoriasis

Main side effect is skin irritation which usually lessens with usage

Excessive use can result in systemic hypercalcaemia

Calcipotriol ointmnet (Dovonex) - once-twice/day

Also available as scalp solution

Not licensed < 6 years old

Use once to twice per day

Maximum use 100g/week

Not suitable for face as too irritating

Calcitriol (Silkis ointment) - once to twice per day

Not licensed < 12 years old

Not as irritating as calcipotriol

So more suitable for flexural and facial psoriasis

Maximum use 30g/day

Calcipotriol with Betamethasone:

Apply daily for 4 weeks

Treatment course can be repeated if necessary

• Dovobet gel:

  • For scalp

  • Max 1-4g daily

  • Can apply to dry scalp overnight and shampoo off in morning

• Dovobet ointment:

  • For skin

  • Max 15g per day

  • Max 30% body surface area

• Enstilar foam:

  • Same ingredients as dovobet but studies claim that the way it is formulated it is more effective

  • Max 15g per day

  • Max 30% body surface area

2/Topical steroids:

Particulalry effective for flexural psoriasis and scalp psoriasis

Be aware of side effects with long term use

Some clinicians would hold back on prescribing potent or extra potent topical steroids (eg dermovate) on psoriatic in case it could potentially lead to a flare of pustular psoriasis on withdrawal

3/Dithranol (aka anthralin)

Can be very irritating

Unsuitable for very fair skinned patients, the face and flexures

In general the crude form is reserved for nurse led treatments in the day unit these days

At home can do “short contact” dithranol therapy: apply to patches for 10-60 minutres then wash off

Useful in resistant, localised plaques

Temporarily stains skin brown/purple/orange and can stain bed sheets/clothes so make sure patient is aware of this (ie get them to wear old pajamas and old bed sheets if using at home)

Tends to be prescribed less these days in light of advances in treatment with systemic agents

4/Coal tar

Comes in many different preparations: creams, ointments, gels, shampoos

Useful for scalp psoriasis (cocois, sebco) and chronic plaque psoriasis

Exorex is a mild preparation that the patient can use at home. Is also good for descaling plaques

Different crude coal tar regimens can be used (often nurse led in day treatment unit or as an inpatient)

Tends to be prescribed less these days in light of advances in treatment with systemic agents

Combination treatments:

Diprosalic: Salicylic acid 3% + Betamethasone

Useful for thick, hyperkeratotic scale (scalp, palms, soles)

• Diprosalic solution:

  • For scalp

  • Few drops once to twice daily

  • Can apply overnight and shampoo off in morning

• Diprosalic ointment:

  • For skin

  • Once to twice daily

  • Max 60g per week

Scalp psoriasis:

Thick adherent scale blocks penetrance of topical therapy

Keratolytic therapy e.g. Diprosalic can help remove scale

If have long hair advise part it and applying directly to the scalp.

Occlusion with a shower cap overnight can help soften scale

Avoid forcefully removing scale as can make it worse due to Koebner phenomenon

The BAD website skinhealthinfo.org.uk has a good video for patients on how to apply treatments in scalp psoriasis (support and resources - video guides)

Other scalp preparations:

Cocois ointment:

• Coal tar 12%, Salicylic acid 2% and sulphur 4%

• Good for psoriasis, seborrhoeic dermatitis and eczema of scalp where scale is thick and adherent

• Rub into scalp, leave overnight with shower cap and wash off in morning

Clobetasol proprionate 0.05% (Etrivex)

• For moderate-severe scalp psoriasis

• Used if regular topical corticosteroids are not working

• Should be applied and left on for 15 minutes uncovered, and washed off

• Do not use >4 weeks at a time

Medicated shampoo preparations to wash out topical therapies include:

• CapasalR shampoo

  • Salicylic Acid 0.5%, Coconut Oil 1%, Distilled Coal Tar 1%

• Polytar shampoo

  • Coal Tar Solution 4%

• Alphosyl 2 in 1 shampoo

  • Alcoholic extract of coal tar 5%

Narrowband uvb

(aka TL-01)

First line treatment

Can be whole body or localised (eg hands and feet)

Useful for chronic plaque and guttate psoriasis

Is time consuming for patient: needs to attend phototherapy service two-three times/week over a period of approx 3 months usually

Individual treatments takes up to 10 minutes

Often for approx 20-30 sessions

Often results in improvement/clearance of psoriasis for a number of months but then can often recur

Risks:

Sunburn type reactions

Photosensitive rashes: eg polymorphic light eruptions

HSV reactivation

Drug photosensitivity

Accelerated photoageing

Increased risk of skin cancer with increasing cumulative dose

Slight increased risk of cataracts

Lifetime limits:

Current recommendation is that ‘ceiling’ of treatments should be about 500 treatments (equivalent to 15-20 course)

If have had this amount of treatments they should get annual review for skin exam looking for skin lesions

PUVA

Second line

Again can be whole body or localised to hands and feet

Tends to be more effective then narrowband uvb with possible longer remission period but carries a higher risk of side effects including increased risk of skin cancer (especially SCC)

UVA is UV radiation of wavelength 320-360nm

‘P’ stands for psoralens. Psoralens make the skin temporarily sensitive to UVA allowing it to be more effective at lower doses

The psoralen can be taken orally, topically applied or mixed in a bathwater solution (often prescribed in psoriasis affecting hands and feet)

Oreal psoralens: 8-MOP or 5-MOP

Tend to give 8-MOP 2 hours prior to treatment

Eye protection must be worn for 24 hours from time of taking tablets- cataract risk

When getting treatment glasses with UVA protection should be used

If get nausea can change to 5-MOP

Lifetime limit:

‘Ceiling’ of 200 treatments recommended

Again if have had over this amount should get annual review

If there is no improvement with topical treatment and phototherapy then may consider a systemic agent

NICE guidance:

Offer a systemic non-biological thrapy to people with any type of psoriasis if:

It cannot be controlled with topical therapy and

It has a significant impact on physical, psychological or social wellbeing and

1 or more following apply:

• Psoriasis is extensive (eg > 10% BSA affected or PASI > 10)

• Psoriasis is localised and associated with significant functional impairment and/or high level of distress (eg severe nail disease or high impact site)

• Phototherapy has been ineffective, cannot be used or has resulted in rapid relapse (defined as > than 50% baseline disease severity within 3 months)

Choice of drugs:

Offer MTX as first choice of systemic agent for people who fulfill the criteria for systemic therapy and have no contraindications to it

Offer ciclosporin as first choice of systemic agent for people who fulfil the crtieria for systemic agent and who:

• Need rapid or short-term disease control (eg psoriasis flare) or

• Have palmoplantar pustulosis or

• Are considering conception (both men and women) and need systemic therapy

Consider changing from methotrexate to ciclosporin (or vice versa) when response to first choice is inadequate

Consider acitretin for adults and in exceptional cases only for children and young people in following circumstances:

If MTX and ciclosporin are not appropriate or have failed or

For people with pustular forms of psoriasis

Regimens:

Methotrexate

Use incremental dosing of MTX (eg start 5mg or 10mg ow) and gradually increase up to effective dose and max of 25mg per week

Assess treatment response after 3 months at target dose and stop if response is inadeaquate (eg decrease of < PASI 75 or a decrease of less than 50% PASI and 5 points in DLQI score)

Ciclosporin

Use to 2.5-3mg/kg/day of ciclosporin

Escalate to 5mg/kg/day if no response to lower dose or when rapid disease control is needed (eg severe, unstable disease)

Assess treatment response after 3 months at optimum dose of ciclosporin and stop treatment if response is inadequate

Use the lowest possible therapeutic dose of ciclosproin to maintain remission for up to 1 year

Consider other treatment if disease relapses rapidly after stopping ciclosporin (ie wiwthin 3 months)

Acitretin

Use incremental doses to minimise mucocutaneous side effects and achieve a target dose of 25mg daily in adults

Consider dose escalation to 50mg dailly when no other treatment options are available

Assess treatment response after 4 months at optiumum dose of acitretin and stop treatment if response is inadequate

Other medications used in psoriasis (I hope to update information regarding these in the future)

Apremilast

Skillarence (a fumaric acid ester)

NICE/BAD criteria for use of biologics in psoriasis:

Offer biologic therapy to people with psoriasis requiring systemic therapy if methotrexate and ciclosporin have failed, are not tolerated or are contraindicated

and

The psorisis has a large impact on physical psychological or social functioning: DLQI > 10

and

One or more of the following apply:

PASI ≥ 10

BAD guidelines also include, but NICE does not:

If it is severe at localized sites and associated with significant functional impairment and/or high levels of distress (eg nail disease or high-impact difficult to treat sites - eg face, scalp, palms, soles, flexures, genital)

Consider a biologic earlier in pathway (eg if MTX has failed, not tolerated or contraindiated) in people who also have active psoriatic arthritis

You then review biologic treatment (at specified timeframe depending on the biologic agent used) and continue if there is:

A 75% reduction in PASI score (PASI 75)

or

A 50% reduction in PASI score (PASI 50) and a 5-point reduction in DLQI

The BAD has good guidelines on use of the biologics in psoraisis

In particular, the supplementary material has good information about each individual biologic agent (Much of the information below is gleaned from this) and it also has a decision aid which can be complementary to information leaflets when discussing with patients about choice of biologic to go with)

https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1111%2Fbjd.19039&file=bjd19039-sup-0001-FileS1.pdf

The BAD also has a UK biologics checklist which outlines what should be done prior to commencing on a biologic, this includes:

Screening lab investigations:

FBC

U&E

LFT

ESR

Hepatitis B/C and HIV serology

VZV serology

ANA/dsDNA

Fasting lipids/glucose

Quantiferon test

CXR

Other important things to do:

Recommend pre-treatment flu and pneumonia vaccinations (also covid vaccines if not up to date)

Ensure cancer screening has been performed appropriate to patient’s age and gender:

Cervical screening: Every 3 years 26-49, 5 years 50-64

Breast screening: Women aged 50-70 every 3 years, over 70 self referral

Mechanism of action of biologics:

Different biologic agents exert their effects by targeting specific cytokines in the psoriasis pathway

Therefore it is useful to have a basic knowledge of the inflammatory pathways involved in psoriasis

Keratinocytes can respond to a trauma or a trigger by releasing substances that can activate dendritic cells

Dendritic cells can determine what happens to a naive T cell and push it down a particular pathway

For instance Th2 cells tend to be involved in eczema and this pathway involves IL 4 and IL 13 cytokines

In psoriasis Th1 cells and Th17 cells are the main T cells involved

Th1 pathway:

IL 12 is realeased by the dendritic cell

This activates Th1 which makes TNFa and IFNy

TNFa classically is involved in anti-tumour activity

IFNy classically is involved in fighting infections (particularly viruses)

Th17 pathway:

Dendritic cells can release IL 1a, TGFb and IL-6

These turn a naive T cell into inducible Th17

Through IL-23 this becomes a pathogenic Th17 population which release IL-17, TNFa and IL-22

These damage keratinocytes which can release more substances to activate dendritic cells creating a cycle

Different biologics target different cytokines in these pathways:

Anti-TNFa agents:

• Adalimumab (generally the first line biologic treatment used due to cost effectiveness)

• Etanercept

• Infliximab

• Certolizumab

IL-12/23 inhibitors:

• Ustekinumab

IL-17A inhibitors:

• Secukinumab

• Ixekizumab

• Brodalumab (IL 17RA inhbitor)

IL-17F inhibitors:

• Bimakizumab

IL-23 inhibitors (p19 subunit)

• Guselkumab

• Risankizumab

• Tildrakizumab

Both Th1 and Th17 pathway lead to increased levels of TNFa
Biosimilars exist for all anti-TNFs except certolizumab

Anti-TNFs still first line due to cost effectivenesss (adlimumab primarily used, etanercept/infliximab used less often)

Usually given subcut (infliximab given IV)

Contraindicated in:

• Active TB

• History of MS/1st degree relative with MS

• NYHA III-IV heart failure

Latent TB is a relative contraindication - could potentially use one if absolutely necessary but should discuss a positive quantiferon test with an ID specialist for treatment of latent TB prior to commencing

Dosing:

Adalimumab: 80mg loading, 40mg at week 1 and then 40mg fortnightly

If have inadequate repsonse at 16 weeks may benefit from increasing to weekly

(Can also increase to weekly if loss of response)

Can consider MTX (if no contraindications/no prior intolerance) to prevent anti-drug antibodies

(6-50% of patients develop antibodes to adalimumab)

Children/young people:

Severe chronic plaque psoriasis in children from 4 years of age who had inadequate response or inapproprpirate for topical and phototherapies

20mg every other week (10-30kg weight)

40mg every other week (for > 30kg weight)

Evaluate response: At 16 weeks and consider stopping if not responding

Half life: Mean 14 days (range 10-20 days)

Rough proportion PASI 90 at 3- months: 41%

Likelihood of staying on it past 1 year: 77-81%

Proportion stopping due to unwanted effects:

2%

Proportion getting serious infection in first 3-4 months: < 1%

Conditions to be hesitant about:

Moderate-severe heart failure, MS (or other conditions affecting nerves)

Does if work for PsA: Recommmended treatment

Certolizumab has a unique molecular structure with no Fc region (‘pegylated’)

Therefore there there is minimal/no placental transfer of certolizumab to foetus

It is the first line biologic agent that should be used if there is intent for conception

Dosing:

Induction: 400mg (x 2 200mg subcut infections) at weeks 0, 2, 4

Maintenance: 200mg every 2 weeks

Can increase to 400mg every 2 weeks with insufficient response

Children/young people: not licensed

Evaluate response: At 16 weeks and consider stopping if not responding

Half life: 14 days approximately

Rough proportion PASI 90 at 3-4 months: 41-48%

Likelihood staying on past 1 year: unknown

Proportion stop due to unwanted effects: 2%

Proportion get serious infection first 3-4 months: < 1%

Conditions to be hesitant about: Moderate to severe heart failure, MS

Does it work for PsA: Licensed treatment

Infliximab and etanercept are not really used as much nowadays due to multiple other options

Etanercept (enbrel, benepali, erlezi)

Dosing:

50mg once weekly

Alternatively 50mg twice weekly may be used for up to 12 weeks followed by 50mg once weekly

Children and young people: From the age of 6

Children dose: 0.8mg/kg (up to max 50mg per dose) once weekly for up to 24 weeks

Evaluate response: At 12 weeks and consider stopping if no response

Half life: Mean 3 days (range 0.3 to 12.5 days)

Rough proportion PASI 90 at 3-4 months: 23%

Likelihood of staying on this past 1 year: 67-73%

Proportion stop due to unwanted effects: 2%

Proportion getting serious infection in first 3-4 months: < 1%

Conditions to be hesitant about: Moderate/severe heart failure, MS

What if I have PsA: Recommended treatment

Infliximab (remicade, inflectra, remsima, zessly, flixabi)

Higher threshold to commence as per NICE guidelines: Requires PASI > 20, DLQI > 18

Dosing:

5mg/kg given as iv infusion at week 0, week 2 and week 6

Maintenance: every 8 weeks thereafter

Children and young people: Not licensed

Evaluate response: At 10 weeks (consider stopping if no response at 14 weeks)

Half life: 8-9.5 days

Rough proportion PASI 90 at 3-4 months: 53%

Likelihood of staying on this past 1 year: 54-74%

Proportion stop due to unwanted effects: 5%

Proportioin gets serious infection in first 3-4 months: Not known

Conditions to be hesitant about: Moderaate/severe heart failure, MS

What if I have PsA: Recommended treatment

(Stelara)

Ustekinumab targets the p40 subunit which is on both IL-12 and IL-23 and therefore targets both the Th1 and Th17 pathways

Dosing:

45mg (90mg if > 100kg) subcut week 0, 45mg (90mg) at week 4

Maintenance: 45mg (90mg) every 12 weeks

Children/young people: from age of 12

Children dose: <60mg: 0.75mg/kg same regime as adults

Indications to stop: Consider if poor response up to 28 weeks of treatment

NICE timelines for evaluating response to therapy: 16 weeks

Half life: Median 21 days (range 15-23 days)

Rough proportion with PASI 90 at 3-4 months: 46%

Likelihood of staying on this past 1 year: 86-92%

Proportion stop due to unwanted effects: 1%

Proportion getting serious infection in first 3-4 months: 1%

Conditions to be hesitant about: No particular condition

What if I have PsA: only whne TNFi failed

BADBIR is a registry of psoriasis patients on various systemic agents including biologic agents

Data from BADBIR is useful as it reflects real world practice with use of these agents compared to the more restricted use of agents in clinical trials

In 2015 a study looking at BADBIR data (of ustekinumab and anti-TNFa inhibitors) showed the largest proportion of patients remained on ustekinumab at 3 years followed by adalimumab, then etanercept, then infliximab

Warren R et al. Journal of Investigative Dermatology (2015). Volume 135

The Th17 reponse is very important in psoraisis

IL-17A is a key cytokine involved in this pathway

(Cosentyx)

Dosing:

Induction: 300mg (x 2 injections) sc injection at week 0, 1, 2 and 3

Maitenance: Monthly injections starting at week 4

Children: not licensed

Indications to stop: Consider if no response up to by 16 weeks

Some with initial partial response may subsequently improve with continued treatment beyond 16 weeks

NICE timeline to evaluate response: 12 weeks

Half life: Mean 27 days (range 18-46 days)

Rough proportion PASI 90 at 3-4 months: 60%

Likelihood of staying on this past 1 year: not known

Proportion stop due to unwanted effects: 2%

Proportion getting serious infection in first 3-4 months: <1%

What are some conditions to be hesitant about: IBD, Recurrent candida

What if I have PsA: Recommended treatment

CLEAR study:

At 52 weeks secukinumab outperformed ustekinumab in multiple domains (including PASI 75, PASI 90, PASI 100 response)

Blauvelt A et al JAAD, 2017 Jan; 76 (1): 60–69

(Taltz)

Dosing:

Induction:

160mg (x2 80mg injections) at week 0

then 80mg at week 2, 4, 6, 8, 10, 12

Maintenance: 80mg every 4 weeks

Children and young people: Not licensed

Indications to stop:

If have shown nor response after 16-20 weeks of treatment

If have initial partial response may subsequently improve beyond 20 weeks

NICE timelines for evaluating response to therapy: 12 weeks

Half life: Mean 13 days

Rough proportion PASI 90 at 3-4 months: 72%

Likelihood of staying on this past 1 year: Not known

What proportion stop due to unwanted effects: 3%

What proportion gets serious infection in first 3-4 months: < 1%

What are some conditions to be hesitant about: IBD, Recurrent candida

What if I have PsA: Recommended treatment

IXORA-S study:

At 52 weeks ixekizumab outperformed ustekinumab in multiple domains (including PASI 75, PASI 90, PASI 100 response)

(Kyntheum)

Dosing:

Induction: 210mg subcut at week 0, 1 and 2

Maintenance: Then 210mg every 2 weeks

Children and young people: Not licensed

Indications to stop: Consider if show no response after 12-16 weeks of treatment

Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks

NICE timelines for evaluating response to therapy: 12 weeks

Half life: 10.9 days

Rough proportion PASI 90 at 3-4 months: 73%

Likelihood of staying on this past 1 year: Not known

Proportion stop due to unwanted effects: 2%

Proportion gets serious infection in first 3-4 months: <1%

What are some conditions to be hesitant about: IBD, Recurrent candida infection

What if I have PsA: Not licensed

AMAGINE-2 study:

At 122 weeks brodalumab outperformed ustekinumab in multiple domains (including PASI 75, PASI 90, PASI 100 response)

So from studies it appears that IL-17 inhibition is clinically superior to both ustekinumab and anti-TNF inhibition

• Inflammatory bowel disease

  • IL-17 is important in gut inflammation

  • 50% of patients with IBD in trials had worsening IBD

  • If develop lower GI symptoms on IL-17 inhibitors should screen for IBD with faecal calprotectin +/- Gastroenterologist opinion

• Increased risk mucocutaneous candidiasis

• Safe in latent TB

  • Can therefore ppotentially proceed with positive quantiferon but should speak to ID team anyway regarding whether latent TB needs treatment

• ?Depression

  • In broadlumab trial two patients had suicide and one with severe depression. When analysed was felt to be circumstantial but still could exercise caution in using these agents in people with severe depression

• Psoriatic arthritis

  • Ixekizumab and secukinumab are also licensed for use in Psoriatic arthritis

In the Th17 pathway IL-23 is upstream from IL-17

IL-23 controls the survival of pathogenic Th17 cells

The IL 23 inhibitors target the p19 subunit of IL-23

(remember ustekinumab blocks p40 which inhibits IL-12 also)

Dosing: 100mg sc at weeks 0 and 4

Then maintenance every 8 weeks

Children: Not licensed

Indications for stopping: Consider if no response after 16 weeks

Half life: 15–18 days

Rough proportioN with PASI 90 at 3-4 months: 68%

Likelihood of staying on this past 1 year: not known

What proportion sop due to unwanted effects: 2%

What proportioin gets serious infection in first 3-4 months: <1%

What are some conditions to be hesitant about: No conditions

What if I have PsA: Not licensed

Dosing:

Induction: 150mg (x2 75mg) sc at week 0, 4

Maintenance: Then every 12 weeks

Children: Not licensed

Evaluate: Consider stopping gf no response at 16 weeks

Some with initial partial response may improve beyond 16 weeks

Half life: Mean 28-29 days

Rough proportion PASI 90 at 3-4 months: 74%

Likelihood of staying on this past 1 year: not known

Proportion stop due to unwanted effects: 1%

Proportion getting serious infection in first 3-4 months: <1%

What are some conditions to be hesitant about: No condition

What if I have PsA: Not licensed

(Illumetri)

Dosing:

Induction: 100mg sc at week 0 and 4

Maintenance: Then every 12 weeks

(If > 90kg: consider 200mg dosing)

In patients with some characteristics (high disease burden, body weight > 90kg,) 200mg may provide more efficacy

Children: Not licensed

Indications for stopping: if no response at 28 weeks

NICE timeline to evaluate response: 12-28 weeks

Half life: Mean 23.4 days

Rough proportion of people with PASI 90 at 3-4 months: 39%

Likelihood of staying on this past 1 year: Not known

What proportion sop due to unwanted effects: 2%

What proportioin gets serious infection in first 3-4 months: <1%

What are some conditions to be hesitant about: no condition

What if I have PsA: not licensed

Psoriasis and pregnancy:

Lots of women’s psoriasis during pregnancy goes in to remission

Remission during pregnancy associated with classical HLA-Cw6 genetic variation (approx 60% may go into remission)

Therefore some women may elect to stop treatment once they conceive

Unfortunately, patients can also have a flare, which is rarer, but not infrequent

Some registry based studies have linked particularly severe psoriasis with adverse maternal and neonatal outcomes although there are some conflicting studies on the subject

Biologics and pregnancy:

Important to advise women of childbearing potential about contraception

In women who are planning conception or are pregnant:

Counsel on importance of controlling severe or unstable psoriasis

Most pregnancies reported in women exposed to TNF antagonists at conception and/or during preganncy have sucessful outcomes with no increase in stillbirths, congenital malformations, preterm births or neonatal infections

Exposure to TNF antagonists at pregnancy may increase risk of maternal infection

Therefore patient should have all her up-to-date vaccinations or at least this should be recommended

Maternal IgG is activley transferred to foetus in 2nd and 3rd trimesters and impact of this on neonatal development and risk of infection has not been adequately studied

In general, live vaccines must be avoided for first 6 months of life in infants born to mothers taking biologic therapy beyond 16 weeks gestation

Certolizumab transfer across the placenta is low or negligible

If decision to use a systemic treatment when planning conception or during pregnancy is made:

• Consider certolizumab as 1st line choice

• Consider using ciclosporin or certolizumab as 1st line when necessary to start systemic agent during 2nd or 3rd trimester

• Consider stopping other biologic therapy in 2nd/3rd trimester to minimize foetal exposure

Breastfeeding:

Can consider reastarting a biologic agent in women wishing to breastfeed

The small amounts of biologic therapy present in breast milk are unlikely to be absorbed systemically by infant

Males and conception:

Regarding TNFa agents there is limited evidence but this shows successful outcomes in most pregnancies with no increased risk of congenital malformations, preterm births or small for gestational age infants

Live vaccines need to be avoided if you are taking immunosuppressants as taking the live vaccine can cause severe infection

General advice:

• Inactivated vaccines should ideally be given at least 2 weeks before treatment, but can be given during immune suppression treatment (may be less effective)

• Live vaccines if needed, should be given at least 4 weeks before treatment with immunosupressants is started

• Live vaccines should not be given to patients taking immune suppression treatment (specific advice for shingles vaccine)

• Live vaccination should not be given within 6-12 months of biologic treatment, 12 months of of other systemic immunosuppression (eg methotrexate, ciclosporin) or 3 months of oral prednisolone at following doses:

> 2mg/kg/day for 1 week or

>1mg/kg/day for 1 month in children or

> 40mg/day for > 1 week in adults

(Can refer to UK Green Book regarding up to date time intervals regarding this for individual agents)

Live attenuated vaccination in infants born to pregnant a women on a biologic agent:

Live attenuated vaccine should be postponed until the postnatal influence of the mother’s immunosuppressive drug treatment on the infant’s immune system has faded away

In the case of foetus exposure to TNF antagonists and other biological medicines beyond 16 weeks gestation: any live attenuated vaccination should be postpone until infant is aged 6 months old (this includes rotavirus, BCG vaccine)

Chickenpox vaccine if required:

Need to give vaccine prior to commencing a biologic agent if not immune

Vaccination involves having 2 separate injections 4 to 8 weeks apart and then need to wait further 4 weeks prior to commencing medicatoin

This may delay starting treatment for up to 3 months

If no protective antibodies and already on an immune-suppressing drug and you have any contact with chickenpox you may need an injection of chickenpox antibodies: VZIG

Shingles vaccine:

Live vaccine to prevent shingles is currently being offered to people aged 70-80 in UK

It is considered safe for patients on low dose immunosuppressive medication to receive this vaccine