IRISH DERM TUTOR

Introduction

Differential diagnosis blistering rash

Diagnostic approach

Superficial Blistering:

• Pemphigus vulgaris

• Pemphgius foilaceous

• Pemphigus erythematosus

• Paraneoplastic pemphigus

• IgA pemphigus
  

Deep Blistering:

• Bullous Pemphigoid

• Cicatricial pemphigoid

• Pemphigoid gestationis

• Epidermolysis bullosa acquisita

• Dermatitis herpetiformis

• Linear IgA disease

The immunobullous diseases are characterised by cutaneous and mucosal blisters

They are due to pathogenic antibodies which target structural antigens in the skin

Good to think about skin anatomy when dealing with blistering disorders

Superficially is the epidermis

Below this is the dermis

Between the two is the basement membrane

The image below shows the epidermis and basement membrane

The basement membrane is represented as a thin line but is a complicated structure

In superficial blistering diseases (eg pemphigus vulgaris) there is often a problem with the connection between the keratinocytes

There are many proteins as noted below involved in keratinocyte adhesion

These collection of proteins are called desmosomes

If any of these are deficient or destroyed you can get superficial blistering

The most clinically relevant tends to be the transmembrane proteins desmoglein 1 and 3

The deeper blistering disorders (eg pemphigoid disorders) involve the basement membrane zone: the inferior part of basal keratinocytes, the basement membrane (lamina lucida and lamina densa) and the upper dermis

The clinical picture we will see  depends on the depth of where the blistering occurs

So if there is a split high up in the epidermis the blisters will be shallow and often will present as erosions rather then intact blisters

If the site of blistering occurs lower for instance around the dermo-epidermal junction the blisters will be much more tense

If the blister occur at or below a certain level in the basement membrane zone (lamina densa) you often get scarring

If I see blisters I try to think what could be causing them:

1/Immunologic:

Superficial blistering:

• Pemphigus group

  • Pemphigus vulgaris

  • Pemphigus foilaceous

  • Paraneoplastic pemphigus

Deep blistering:

• Pemphigoid group:

  • Bullous pemphigoid

  • Mucous membrane pemphigoid

  • Pemphigoid gestationis

• Dermatitis herpetiformis

• Linear IgA disease

• Epidermolysis bullosa acquisita

2/Inherited:

• Epidermolysis bullosa (not acquired form)

3/ Infective: 

• Viral

  • HSV, herpes zoster

  • Hand, foot, mouth disease (enteroviruses)

• Bacterial

  • Bullous impetigo (staph toxin causes the blisters)

  • Staphyloccal scalded skin syndrome

  • Severe cellulitis/necrotising fasciitis

• Bullous tinea

• Bullous scabies

4/ Metabolic:

• Porphyria cutanea tarda

• Diabetic blisters

5/Drug related:

• Steven Johnson’s/Toxic epidermal necrolysis

• Fixed drug eruption

7/Acute Dermatitis

• Contact dermaitits (eg severe hair dye allergy)

• Phyto-photo dermatitis (plant dermatitis)

• Vescicular hand dermatitis

8/ Other inflammatory conditions

• Bullous lupus

• Bulloud tinea

9/Miscellaneous

• Oedema blisters: eg gross oedema in the legs

• Trauma - burns, friction, scalds

• Insect bites

Going forward on this site I will only discuss the approach to the Autoimmune Bullous Disorders (AIBD)

As mentioned before they are a group of disorders which occur due to antibodies directed against antigens either in the epidermis, the basement membrane zone or the upper dermis

To come to the correct diagnosis you should have a standardised approach to these rashes which may involve some or all of the following:

• Clinical assessment: History, exam, disease activity assessment

• Biopsy for H&E

• Biopsy for Direct immunoflourescence

• Serologic detection and differentiation of circulating antibodies

I will mention a few different antibodies in the next few paragraphs but I will go into them in more detail later when discussing the relevant conditions

Skin biopsy:

• H&E

• DIF

• +/- salt split skin test as appropriate

Biopsy for H&E:

Limited diagnostic value but can give some clues to the diagnosis based on:

The level of the split -

• Subcorneal

• Intraepidermal

• Subepidermal split

The nature of the inflammatory infiltrate:

• Neutrophils

• Eosinophils

• Lymphocytes

• Cell poor

Direct immunofluorescence:

This is performed on tissue from a biopsy

This techniques is used to identify antibodies/proteins (IgG, IgM, IgA, C3 +/- fibrinogen) which is bound to tissue from a biopsy specimen and the patterns of how they are deposited

This is done by

1. Adding an antibody labelled with dye to the biopsy specimen which then binds to the above antibodies or proteins if present

2. The pattern of staining is then seen using a fluorescent microscope

It is used to narrow down the diagnosis according to the deposited immunoglobulin subclass and the binding pattern seen

Binding pattern:

In the pemphigus diseases (superficial) the antibodies will bind to the keratinocytes and form a ‘chicken wire pattern’

In the pemphigoid diseases and other sub-epidermal conditions the antibodies will bind to the DEJ

However, it provides limited information on the specific antigens that are targeted

Salt split skin test:

Can help differntiate bullous pemphigoid from epidermolysis bullosa acquisita, mucous membrane pemphigoid and some other conditions

Can incubate the skin biopsy in 1mol/L of salt prior to DIF which causes a split at the lamina lucida (think of the ‘loose lucida’)

In bullous pemphigoid the IgG will be found on the blister roof (epidermal side of split skin)

In EBA and cicatricial pemphigoid the IgG will be found on blister floor (dermal side of split skin)

Serologic detection differentiation of circulating antibodies:

Check this with a blood test

Conventional method:

• Initially do indirect immunoflourescence (IIF) microscopy as a screening test

• This is followed by a more antigen-specific serologic assay (eg ELISA) based on the clinical suspicion and IIF screening results

Indirect immunofluorescence microscopy:

Highly sensitive so good for screening purposes but not as specific for determiniation of the causative autoantibody as ELISA

Is a technique used to detect circulating antibodies in a patient’s serum blood test:

1. Antibodies/complement (eg IgG, IgM IgA, C3 ) from the patient’s serum (primary antibodies) bind to the target molecules (the substrate) in pre-prepared tissue samples (eg monkey oesophagus)

2. Then antibodies labelled with dye bind to the above antibodies

3. The pattern of staining then seen using a fluorescent microscope

Choice of substrate tissue to use may depend on clinical suspicion

Classic prepared tissues:

• Pemphigus vulgaris - monkey oesophagus - monkey oesophagus has high expression of Dsg 3 (think that monkey’s are vulgar, throw poo)

• Pemphigus foilaceous - guinea pig oesophagus - good for dsg 1 (think of a guinea pig running in foliage)

• Paraneoplastic pemphigus - rat bladder - plakins (envoplakin, periplakin, desmoplakin) are highly expressed in bladder (think radiation causes cancer, rats often roam in radioactive areas)

• Dermatitis herpetiformis -primate liver best to visualise IgA against endomysium

Antigen-specific serologic assay:

To get an even more specific diagnosis you can identify antibodies to a specific antigen using ELISA, immunoblot or monospecific IIF

I will only discuss ELISA as it is increasingly being used

It is based specific antigen substrates that have been made by recombinant expression systems

With this blood test you can identify specific antibodies in blood to specific antigens and you can quantify the levels of antibodies circulating within the blood (this can sometimes give an indication of disease activity)

I will discuss the following antibodies later when releavant but different ELISA systems can detect antibodies against:

• Dsg 1 and 3 - Pemphigus vulgaris

• Envoplakin - Paraeneoplastic pemphigus

• BP 180, BP 230 - Bullous pemphigoid

• Collagen VII - Epidermolysis bullosa acquisita

• Deamidated gliadin and transglutaminase - Dermatitis herpetiformis

• Anti-laminin y1 (specialised labs) - anti-p200 pemphigoid

• Anti-laminin 332 (specialised labs) - cicatricial pemphigoid (subtype associated with cancer)

Can now do panels where you cover multiple antigens in one go and this could be used as an alternative to the initial screening IIF technique discussed above

As mentioned above, if the split occurs superficially the patient will present with erosions.

Keratinocytes are held together by various proteins including proteins called desmosomes

There are multiple different proteins in the family of desmosomes

The most clinically relevant desmosomes include desmoglein 1 and 3

Significant levels of Desmoglein 3 are in found in the mucus membranes, as well as the skin

Desmoglein 1 is found mostly in in the skin and not so much in the mucus membranes

Pemphigus foilaceous occurs due to antibodies against desmoglein 1

• So mucus membrane involvement is rare 

Pemphigus vulgaris occurs due to antibodies forming against desmoglein 3 and/or desmoglein 1

• As desmoglein 3 is involved mucus membrane involvement is common

Split in pemphigus foilaceous tends to be high (subcorneal/granular)

Split in pemphigus vulgaris tends to be deeper (suprabasilar)

Can occur across a wide range of ages but peak frequency is the 3rd to 6th decade

Autoimmune disease due to antibodies to desmoglein 3 +/- desmoglein 1

Get shallow blisters,erosions and crusting on skin and mucus membranes

Distribution can often initially affect the scalp, face and be in a shawl-like distribution on the upper central torso

Often presents with oral erosions (50-70% of cases) and genital lesions as demoglein 3 is found in a high proportion in mucus membranes

Lesions can be painful and slow to heal (can make eating/drinking difficult)

Clinical phenotype may depend on predominant antibodies, for example:

Mucosal only disease - correlates with high levels of circulating anti-Dsg 3 autoantibodies

Cutaneous only disease - correlates with predominant anti-Dsg 1 autoantibodies

Most frequently see mucocutaneous disease with presence of both anti-Dsg 1 and anti-Dsg 3 antibodies

Investigations:

Skin biopsy:

Biopsy of area of blistering and area of surrounding skin - for H&E

Biopsy of peri-lesional area - for DIF

If have isolated oral disease take specimen from perilesional mucosa for H&E and a DIF sample from an uninvolved area (preferably buccal mucosa)

H&E:

Shows split (called acantholysis) just above the basal layer of the epidermis (suprabasilar)

The basal keratinocytes lose contact with their neighbours but stay in contact with the basement membrane via the hemidesmosomes giving a row of tombstones appearance

Direct Immunofluorescence: 

In pemphigus vulgaris see granular or linear IgG and/or C3 at the surface of epidermal keratinocytes (‘intercellular staining’) - ‘chicken wire pattern’

Indirect immunofluorescence:

Monkey oesophagus or human skin classically used as the substrate

Again see chicken wire pattern of staining

Some labs can now do indirect IF microscopy on cells that recombinantly express Dsg 1 and Dsg 3 on skin surface

ELISA:

Can quantify amount of desmoglein 3 and desmoglein 1 in blood

The amount of desmoglein seen can correlate with disease activity and severity

Desmoglein 1 antibody levels can be associated with skin severity

Desmoglein 3 antibody levels can be associated with oral severity

Titres usually fall with treatment and disease remission

Pemphigus vulgaris is more serious then bullous pemphigoid and pemphigus foilaceous and should be dealt with swiftly

 Treatment:

In pemphigus B cells produce antibodies which target desmogleins which connect the epidermal cells

Can think of B cells as factories making antibodies when thinking of the various treatments

• Rituximab is an anti-CD20 antibody that targets B cells

  • Therefore it ‘kills the factories’ making antibodies

• Other immunosuppressive agents (prednisolone, MMF, Azathioprine) slow down factory production of antibodies

• IVIG induces the destruction of the antibodies

Treatment options include:

The following algorithm has been adapted from: S2K guidelines on management of pemphigus vulgaris and foilaceous by the EADV. JEADV 2020

Recent studies have suggested that rituximab with or without steroids has better rates of remission off steroids and less severe side effects than the conventional treatment of oral steroids with or without steroid sparing agents

These guidelines came out prior to the covid pandemic. Rituximab is a high risk medication for covid so this may alter how these guidelines should be applied

Conventional immunosuppressive agents that tend to be used in pemphigus are azathioprin and mycophenolate mofetil

Can be used first line when rituximab is not available/permitted or in patients with contraindications to rituximab

Mild pemphigus:

1st line:

Use rituximab with or without prednislone 0.5mg/kg/day

Taper steroids over 3-4 months

Alternative 1st line:

Use prednisolone 0.5-1mg/kg/day with or without azathioprine or mycophenoate mofetil (MMF)

Disease control achieved? Yes

Continue prior treatment with taper in steroids

• To stop after 3-4 months if used rituximab

• Slower taper if rituximab not used

Second line treatment:
If treated prednisolone without riuximab:

Add rituximab and taper steroid over 3-4 months

If treated prednisolone 0.5mg/kg/day and rituximab:

Increase prednisolone to 1mg/kd/day

Moderate to severe Pemphigus vulgaris:

1st line:

Rituximab and prednisolone 1mg/kg/day

Taper steroid over 6 monthsS

Alternative first line:

Prednisolone 1-1.5mg/kd/day with or without steroid sparing agent (azathioprine or MMF)

Disease control at 3-4 weeks:

Can give maintenance rituximab at 6 months in the following cases:

• 500mg or 1g in patients in complete remission but who intially had severe pemphigus or who have high level of anti-Dsg antibodies at 3 months

• 1g x 2 2 weeks apart in patients without complete remission

Can consider maintenance rituximab at 12 and 18 months in following cases:

In patient in complete remission in particular in patients with still positive desmoglein antibodies

After the 18 months there is not sufficient evidence to recommend rituximab in patients in complete remission

However should continue to monitor levels of circulating anti-desmoglein and could consider additional infusion if antibodies re-increase after an initial disapperance

No disease control at 3-4 weeks:

If treated with rituximab and pred (1mg/kg):

• Give pred 1.5mg/kg or IV steroid pulses

If treated with pred (1mg/kg) alone:

Give pred 1.5mg/kg and give rituximab or azathioprine/MMF

If treated with pred (1.5mg/kg) alone:

Add rituximab or azathioprine/MMF

Severe/refractory pemphigus:

• IVIG:

  • 2g/kg/cycle over 2-5 days every 4 weeks

  • Aseptic meningitis is a rare side effect of treatment

  • Need to check IgA before giving as complete IgA deficiency is a contraindication (as can get anaphylaxis if given)

• IV corticosteroid pulses

  • Methylprednisolone 0.5-1g/day over 3 days

  • 3-4 week intervals

• Immunoadsorption

  • Minimum of 2 cycles over 3-4 days

  • 4 weeks apart
    
    

Again most commonly occur in people between 50-60

Autoimmune disease due to antibodies against desmoglein 1

Desmoglein 1 not found much in mucus membranes so there little or no involvement of mucous membranes

So skin is involvement is the main clinical manifestation

Due to the very high level of the split (subcorneal/granular) intact blisters are rarely seen

Clinical:

Classically presents with crusted erosions in a V shape/ shawl-like distribution on the chest and can affect the face and scalp in a seborrhoeic like distribution (pemphigus vulgaris can occur in a similar distribution)

Erosions often not as painful as pemphigus vulgaris but can itch/burn

Not as severe as pemphigus vulgaris

Can be drug induced- NSAIDs, ACEi , Nifedipine

Investigations:

Skin biopsy:

Biopsy of area of blistering and area of surrounding skin - for H&E

Biopsy of peri-lesional area - for DIF

H&E: Split occurs in the upper layers of epidermis (subcorneal/granular layer)

Ddx of intra-epidermal sub-corneal split:

Pemphigus foilaceous (positive DIF)

Bullous impetigo

Staphylococcal scalded skin syndrome

Direct immunofluorescence:

Usually intercellular IgG with or without C3

Indirect immunofluorescence:

Antibodies to dsg 1

Classic substrate used: Guinea pig

(Think of guinea pigs running in the foiliage)

Treatment:

Mild:

• Topical steroids: alone only for very limited lesions

• Dapsone, can be combined with topical steroids

• Systemic steroids (pred 0.5-1mg/kg/day)

• Rituximab alone or with topical/oral steroids

If moderate/severe can use similar algorithm as mentioned for pemphigus vulgaris (according to S2K guidelines on management of pemphigus vulgaris and foilaceous, EADV. JEADV 2020

(Also known as Senear-Usher syndrome)

Is a localised form of pemphigus foilaceous

Get scaly and crusted lesions across the malar area of the face and in other seborrhoeic areas

May remain localised for years or evolve into a more generalised pemphigus foilaceous

It is called pemphigus erythematosus as it shares immunologic features of both lupus erythematosus and pemphigus

Get IgG and C3 seen on cell surfaces of keratinocytes and in the basement membrane zone

May have serologic findings suggestive of SLE especially positive ANA

Less common (but can be very severe) form of pemphigus

Antibodies against periplakins, envoplakins, desmoplakins, Dsg 1 , Dsg 3

Patients are often very unwell

Poor prognosis

Typically starts with painful oral erosions - can get severe recalcitrant ulceration with pan stomatitis and hyperplastic mucosa

The rash is often polymorphic with blisters, erosions, papules and plaques

Can look like:

• Pemphigus/pemphigoid

• Erythema multiforme

• A lichenoid type of rash like lichen planus

Can affect other organ epithelia (eg lungs, GIT)

Can be due to an abnormal B or T cell response to an underlying malignancy that targets specific keratinocytes

[B cells- more blisters/erosions]

[T cells- more lichenoid type reactions]

Associated cancers tend to be haematological malignancies:

Lymphoma (40%)

CLL (approx 30%)

Castlemans disease (10%)

Thymomas, spindle cell neoplasms, sarcomas, waldenstroms macroglobulinaemia

[Note:

Castleman disease is a rare disorder that involves an overgrowth of cells in body’s lymph nodes.

The most common form of the disorder affects a single lymph node (unicentric Castleman disease) usually in the chest or abdomen

Multicentric castleman disease affects multiple lymph nodes throughout the body and has been associated with HHV 8 and HIV]

There are two types of IgA pemphigus:

1. Subcorneal pustular dermatosieu type (SPD)

2. Intraepidermal neutrophilic type (IEN)

Both types associated with intercellular IgA deposits on immunoflourescence

But there is NO ACANTHOLYSIS on histology (unlike pemphigus vulgaris, pemphigus foilaceous and paraneoplastic pemphigus)

Clinical:

SPD clinically presets as serpiginous vesicles and pustules

IEN classically presents as flaccid pustules and bullae arranged in an annular, polycyclic (sometimes referred as sun-flower like) arrangements usually in intertriginous areas

The pustules tend to quickly rupture and you get an annular crust over the plaque

Commonly affects flexural areas like axilla and groin but can be more widespread

Associations:

Monoclonal IgA gammopathy

Multiple myeloma

Others reported: HIV, Sjogrens, RA, Crohn’s

Investigations:

H&E:

Intra-epidermal neutrophillic infiltration

Little to no acantholysis - have mild loss of cohesion between keratinocytes

Subcorneal pustular dermatosis subtype - increased intensity of IgA autoantibodies in the upper surface of the epidermis.

Intraepidermal neutrophilic - inflammatory infiltrates, primarily in either the entire or lower part of the dermis.

DIF:

IgA on epidermal cell surfaces

IIF:

Positive circulating IgA

Treatment options:

Steroids: topical and oral (0.5-1mg/kg)

Addition of Dapsone far superior to just steroids alone (dapsone often good for treatments with neutrophilic infiltrates)

Other agents: Colchichine, sulfapyridine, acitretin, PUVA

Less often: MMF, adalimumab (TNf-alpha is involved in activation of neutrophilic infiltration of epidermis so may hinder further progression of IgA pemphigus)

Ddx:

• Subcorneal pustular dermatosis (aka Sneddon Wilkinson disease)

  • Sterile pustular lesions that erupt in cyclical patterns

  • Like IgA pemphigus the pustular lesoins coalesce in an annular pattern and burst to form crusted plaques

  • Similar area of distribution - groin, trunk, axilla and avoid mucous membranes

  • Histology shows perivascular infiltration of neutrophils and spongiosis

  • DIF negative for IgA

• Pemphigus foliaceous

  • DIF is key - pemphigus foliaceous demonstrates IgG to DsG 1

• Bacterial skin infections

• Linear IgA Disease

Prognosis:

Much milder and limited disease compared to classic pemphigus

If the split occurs deeper the blisters clinically will be tense

Often due to attack of proteins in the Basement membrane zone

The basement membrane zone is complex with multiple proteins within it

Different clinical conditions occurs due to lack of specific proteins through attack or congenital lack of these proteins (epidermolysis bullosa congenita)

The most common immune blistering disease in the elderly

Blistering is ‘subepidermal’

Blisters are tense and stable (can be filled with blood)

Can often start with an urticarial type rash which may persist for a few weeks/months prior to the blisters appearing

 It is more prevalent in people with neurological disease (eg stroke/parkinson’s)

It is due to antbodies (IgG) attacking proteins in the basement membrane

Targets are to proteins associated within hemisdesmosome:

BP 180 (aka BP Ag2 or Type XVII collagen which is found in the CNS also)

Or less frequently BP230

Investigations:

Perform a skin biopsy with bit of blister and surrounding skin

H&E:

Split under the epidermis seen

‘Subepidermal bullae’ containing eosinophils and/or neutrophils

Ddx: Sub-epidermal split with eosinophils:

Bullous pemphigoid

Bullous drug eruption

Bullous arthropod bite

Direct immunofluoresence:

Linear IgG and/or C3 along the dermoepidermal junction

(occasionally IgA and IgE)

Salt split skin test:

Causes a split in the lamina lucida

In bullous pemphigoid the IgG will be found on the blister roof (epidermal side of split skin)

Sometimes IgG may be seen on epidermal and dermal side

In EBA and cicatricial pemphigoid the IgG will be found on blister floor (dermal side of split skin)

ELISA:

Can detect:

• Anti-BP 180 (aka BPAG2/Type XVII collagen)

• Anti-BP 230 (aka BPAG1)

Prognostic factors in bullous pemphigoid:

Treatment can be tricky as patients usually elderly (mean age 80)

Often have poor general health

Deletrious prognostic factors:

• Older age

• Cardiac insufficiency

• Dementia

• Past history of stroke

• Poor general condition

• Use of high doses of corticosteroids 

Management:

Generally get bullous pemphigoid in patients with old age who may have multiple co-morbidities so need to this in to account when considering best treatment (eg avoiding oral steroids in patients with cardiovascular disorders)

There are BAD guidelines for treatment of bullous pemphigoid from 2012 and more recently updated S2K guidlines for the management of bullous pemphigoid initiated by the EADV (2022)

As the European guidelines are more recent I have taken much of the below information from them

As with pemphigus vulgaris you have multiple medications you can consider when thinking about managing bullous pemphigoid:

Other potential therapies that may be considered in treatment resistant bullous pemphigoid include the following but none of these treatments are validated:

• Rituximab

• Omalizumab

• Dupilumab

• IVIG

• Immunoadsorption

  
  

In general oral and topical steroids have the most evidence behind them regarding management of BP and tend to be very effective at getting blister control but as already mentioned can have a considerable side effect profile so need to take this in to consideration

Localized (ie lesions involving only one body site):

Topical dermovate cream 10g once daily to invovled area

Continue until 15 days after control of disease activity (CDA)

Followed by progressive tapering over 4 months

• CDA definition - the point at which new lesions or pruritic symptoms cease to form and established lesions begin to heal

Mild and moderate BP:

Mild/moderate BP can be defined as occurence of ≤ 10 new blisters/day or the presence of few non-bullous inflammatory lesions in different localizations

Can also use a scoring system called the BPDAI which divides the body up in to different sections and quantifies the amount of erosions/blisters, urticaria/erythema and damage (eg pigmentation)

• BPDAI < 20 - mild

• BPDAI <57 - moderate

The two regimens that have shown significant benefit are:

1. High potency topical steroids: Initial dose dermovate 20-30g once or twice daily to whole body sparing the face

2. Medium dose of oral steroids: Initial dose 0.5mg/kg/day

Topical steroids:

Once CDA is acheived continue at same dose for 15 days then progressively taper over a 4-12 month period, example of taper is:

• Daily treatment 1st month

• Alternate day treatment 2nd month

• Twice weekly treatement 3rd month

• Once weekly treatment 4th month

• Then:

  • Consider maintenance treatment x 8 months (eg 10g once per week to previously affected and surrounded areas)

    Or

  • Stop treatment (slightly higher risk relapse but improved safety profile)

If didn’t get disease control after 1-3 weeks increase up to 40g/day

Oral steroids:

High dose oral steroids (1mg/kg/daily) has been shown to be effective in studies but is associated with higher mortality and increased side effects compared to topical treatment so is not recommended

Starting dose of 0.5mg/kg/daily recommended in treating mild/moderate and severe BP

• Reduce this 15 days after CDA is achieved

• Taper gradually over 4-6 months with the aim of achieving minimal therapy (0.1mg/kg/day)

• Stop if in complete remission under minimal therapy for 3-6 months

• In case of relapse during this period increase the dose to the previous level

Then if oral steroids and other immunosuppressive agents are contraindicated or as an adjunct to topical steroids the following anti-inflammatory medications ‘may be recommended’ in mild to moderate BP (but generally not in severe BP as not deemed to be effective):

Doxycycline:

Was deemed beneficial in a RCT that compared doxycycline and oral prednisolone (BLISTER trial, n=253)

• People were able to apply strong topical steroids to active lesions during the study and received doxycycline 200mg daily (initially) or prednisolone 0.5mg/kg/day for 6 weeks (if they had poor control on doxycycline they could then switch to steroid)

• At 6 weeks 74% achieved what was considered reasonable control in doxycycline group (3 or fewer significant blisters) compared with 91% in the prednisolone group (which was deemed non-inferior according to the pre-classified noninferiority margin of 37%)

• In addition there were significantly fewer adverse events in the doxycycline gorup at 52 weeks

However some smaller studies since have suggested that doxycycline alone is often not effective in achieving disease control and often prednisolone is required

The EADV guidelines suggested that no consensus could be reached among the experts with regard the use of doxycycline in the BP

Therefore they ‘may be considered’ in combination with topical steroids in particular in patients with contraindications to oral corticosteroids or immunosuppressive treatments with a mild or moderate BP since the benefit is limited in severe BP

Doxycycline can be used in combination with nicotaniamide (up to 2g/day orally)

Dapsone:

Again a consensus could not be reached but suggested it could be considered in patients with contraindications to oral steroids or immunosuppressive treatments with mild and moderate BP

But need to be very careful prescribing dapsone in older patients with cardiovascular disease (as they would be more sensitive to any anaemia that could occur with dapsone)

Methotrexate:

Tend to use low dose (5-12.5mg weekly subcut) due to the increased risk of complications in an elderly population

In a RCT of 300 patients the 1st line use of MTX combined with topical steroids for one month allowed a reduction in the 9 month relapse rate from 42% to 25% relative to steroid alone

Severe BP (> 10 new blisters/day on multiple anatomic sites or BPDAI ≥57):

Two first line options:

High potency topical steroids: Initial dose dermovate 30-40g twice daily to whole body (sparing face and ano-genital area)

Medium to high dose of oral steroids:

• Initial dose 0.5mg/kg/day - only 50% will achieve CDA so then have two options:

  • Increase oral predisolone to 0.75mg/kg/day

    Or

  • Add topical dermovate

Extensive/Severe BP: (>10 new blisters per day on multiople anatomic sites or inflammatory lesions covering large body surface areas)

Start with:

Super potent topical steroid: Dermovate 30-40g/day [20g/day if <45kg]

Give over two applications over entire body (sparing face)

Initial treatment reduced after 15 days of disease control (new lesions/pruritic symtpoms cease to form, established lesions begin to heal)

Medium dose prednisolone 0.5mg/kg/day

Maintenance

Consider Methotrexate 10-15mg/week

Consider Tetracyclines but disease may be too severe to be effective

? MMF (if CI to MTX)

Much rarer than bullous pemphigoid

Again a disease of the elderly

It can affect the skin only, mucous membranes only or both the skin and mucous membranes (such as oral mucosa and conjunctiva)

When only mucous membranes involved may be referred to as mucous membrane pemphigoid

When only the ocular membranes are involved may be referred to as ocular pemphigoid

Can also oesophagus, trachea and genital area

Get long term scarring so want to get under control ASAP

There is a risk of complications such as blindness and airway compromise so requires systemic therapy

Investigations:

Many antigen targets have been implicated in cicatricial pemphigoid

a6b4 integrin - ocular

Laminin-332 (5) - increased risk of associated cancer

BPAG2 (collagen XVII):

The carboxy terminus affected which spans the lamins densa and projects the lamina lucida

This is deeper than the NC16a terminus

(bullous pemphigoid, linear IgA bullous dermatosis (LABD), pemphigoid gestationis tends to target the NC16A terminus)

H&E:

Subepidermal blister with mixed inflammatory infiltrate (neutrophils, eosinophils)

Plasma cells more common in mucosal biopsies

Ddx:

Bullous pemphigoid, LABD, EBA

DIF:

Typically IgG and C3 in a linear band at the BMZ

Linear IgA at BMZ occasionally seen

IIF with salt split skin test:

IgG or IgA will tend to show a dermal pattern

But again it can also show an epidermal pattern

ELISA:

Some labs may be able to test for anti-BP 180 carboxy terminal domain and anti-laminin-332

Treatment options:

Topical therapies for mild skin and oral mucosal diseae only an option

Dapsone

Oral steroids (with or without dapsone)

Other agents:

Azathioprine, MMF, Cyclophosphamide, IVIG, TNFa inhibitors, Rituximab

Brunsting-Perry Cicatricial Pemphigoid:

Is a rare variant of cicatricial pemphigoid most commonly seen in elderly males

Get pruritic, recurrent crops of vesicles which heal with atrophic scars

Vesicles mainly confined to the head and neck

Blistering disorder that can occur during pregnancy

Postulated that HLA mismatch between mother and foestus may trigger an immune response that cross-reacts with maternal skin

Characterised by IgG antibodies directed against BP Ag 2 in the BMZ

Antibodies to BP230 can be present in about 10%, the significance is unclear

Often presents in a prebullous phase involving urticarial plaques and papules on the abdomen that characteristially involve the periumbilical skin (may start here)

The rash may then spread to the rest of the torso, the intertriginous areas and extremities

The face, palms and soles usually spared

Mucosal involvement in less than 20% of cases

Can occur any time between 4 weeks gestation and 5 weeks postpartum with the majority presenting in the 2nd and 3rd trimester

Onset in 1st or 2nd trimester can lead to adverse pregnancy outcomes:

Decreased gestational age at delivery

Preterm birth

Low birth weight

But overall it has a generally good foteal prognosis

Is associated with other autoimmune diseases ad more rarely with trophoblastic tumours (choriocarcinoma, hydatidiform moles)

H&E:

Identical to bullous pemphigoid

DIF:

Linear C3 in all cases, IgG only seen in approx 25% of cases

ELISA:

Antibodies to NC16a domain of BP 180 seen(very sensitive and specific)

There are many inherited forms of epidermolysis bullosa

This type is an acquired mechanobullous disorder

Get antibodies to type collagen 7 which constitutes part of the anchoring fibrils which attach the basement membrane to the underlying dermis

Clinical:

Get non-inflammatory tense blisters occur at sites of trauma/friction (hands, wrists, ankles, knees) Can get mucous membrane involvement also

As, split is below the lamina densa it scars with scarring milia and atrophic scarring

May get some mucous membrane invovlement and in some cases can get oesophageal stenosis

H&E:

Sub-epidermal blistering

‘Often cell poor’ (minimal inflammation)

DIF:

Linear IgG +/- C3 +/- IgA in Basement membrane

Another method that may help differentiate EBA from the pemphigoid diseases is the serration pattern

This involves looking at the linear flourescence and if the overall pattern looks like:

A repeating ‘u’: think Epidermolysis bullosa acquisita or bullous SLE

A repeating ‘n’: think of the other pemphigoid diseases -BP, MMP, anti-p200 pemphigoid, linear IgA dermatosis

IIF with salt split skin test:

Antibodies tend to attach to the dermal side

ELISA:

Positive antibodies against Collagen VII

Usually have a preceding diagnosis of SLE but can be its first presentation

IIF on salt split skin specimens:

Deposition of antibody on dermal side

 Get very itchy small blisters

Blisters are very fragile and often presents as erosions and crusts

Tends to occur: around elbows, knees, over buttocks, scapulae

Tends to be quite symmetrical

Is related to coeliac disease:

Get IgA production to the protein gliadin. These immune complexes can then be deposited in the skin at the lamina lucida level

The majority (>90%) also have gluten-sensitive enteropathy

Patients may remain completely symptom free

Investigations:

Skin biopsy: Sub-epidermal blisters. Inflammatory cells in dermis

IF: IgA deposits in the dermal papillae on DIF

Coeliac antibodies: anti-TTG, Anti- endomysial

Small intestinal biopsy: looking for villous atrophy

Treatment:

Gluten-free diet

Dapsone: works very quickly (within 3 days)

 More common in childhood and elderly

Blisters affect skin and mucous membranes

Blisters more stable then DH

Blisters often seen on outside of a red inflamed area giving a ring like structure

Causes:

Doesn’t have same association with coeliac disease

Has been reported in IBD and haem cancers

Can be drug induced

Investigations:

H&E: subepidermal blistering with inflamm infiltrate in dermis

DIF: IgA along the BM of epidermis in a linear pattern

Treatment:

Dapsone effective again

Metabolic:

 Porphyrias:

Metabolic disorders caused by altered activity of enzymes in the heme biosynthesis pathway

Porphyria can be subdivided into 3 main groups based upon clinical presentation:

Acute intermittent (hepatic) porphyrias - neurological symptoms

Cutaneous porphyria

Acute and cutaneous - neurologic and cutaneous symptoms

Acute hepatic: Acute intermittent porphyria

Acute and cutaneous: Hereditary coproporphyria, variegate porphyria

Cutaneous: PCT, CEP, EPP, Hepatoerytrhopoietic porphyria

Three ways in which porphyrias present in the skin:

• Immediate painful photosensitivity:

  • Erytrhopoeitic porphyria

• Mutilating photosensitivity

  • Congenital erythropoeitic porphyria (Gunter’s disease)

  • Other rare severe homozyghous porphyrias

• Bullous porphyrias - skin fragility and bullae

  • Porphyria cutanea tarda

  • Variegate porphyria

What causes Porphyria?

Haem is found in haemoglobin, myoglobin and other haem protens such as cytochromes

Haem is made from the precursors glycine and succinyl CoA

These are converted to haem by 8 chemical reaction steps

Each step is catalysed by a specific enzyme

If one enzyme has reduced activity and is not working properly you will get an acculumation particularly of the biochemical on which the enzyme works

If the biochemical is a porphyrin as in the case of some of the intermediaes above then porphyrins accumulates

Acute porphyrias occur due to direct cytotoxic effect of ALA and PBG on neural tissue

Cutaneous porphyrias due to toxic metabolites poteniated by sunlight (UV causes free radical formation)

AIP: PBG deaminase (aka uroporphyrinogen 1-synthase)

CEP: UPC

PCT: UROD

HC: Coproporhyringoen

VP: PPO

EPP: Feroocheletase

Mechanism of action

Porphyrins can be phototoxic

A photon of visible violet light (approx 408-410nm) is absorbed by porphyrin

This causes the porphyrin to be in an excited state (called a ‘triplet state’)

This can then react with oxygen and turn oxygen into its activated state (‘singlet oxygen’)

The singlet oxygen then directly damages local tissues

So think of porphyrins as little machines that convert visible light photons into tissue damage via singlet oxygen

As mentioned previously porphyrias can present differently in skin eg,

• EPP causes an immediate, painful photosensitivity

• PCT causes fragility and bullae particularly on back of hands

One hypothesis is this difference is due to the solubility of the different porphyrins due to the number of carboxylate groups (COOH) each porphyrin has which alters the solubility of the porphyrin

Uroporphyrin is water soluble

Protoporphyrin lipid soluble (and not water soluble)

In PCT, uroporphyrin accumulates in the skin and as it is water soluble it can diffuse up to upper dermis

It is then activated by light and the phototoxic reaction occur in the upper dermis causing a split with blistering

In EPP, the protoporphyrin accumulates in the red cells and does not diffuse further than the endothelial lining of small blood vessels.

Light produces endothelial necrosis in the upper dermis causing typical pain and oedema

 PCT is the commonest of the porphyrias

Due to an acquired or inherited deficiency in the activity of the hepatic enzyme uroporphrinogen decarboxylase which usually converts uroporphyringoen III into Coproporphyrinogen III

Decrease in activity of this liver enzyme can be multifactorial

It is due to an inhibitor UROD called uroporphomethene

This is produced particularly in the presence of an oxidising environement and increased iron in the liver

Certain conditions predispose to an environment in which this inhibitor is produced leading to PCT:

• Haemochromatosis (20%)

• Hepatitis C (15%)

• Alcohol (50%)

• Oestrogen: eg HRT (50% females)

• Smoking
  
  

So in summary, inhibition of UROD leads to a build up of uroporphyrinogen III
 

Genetic factors may be present:

A UROD mutation which is seen in 25% of patients makes the enzyme not as effective

Therefore it requires less inhibitor activation to produce the disease so often get the disease at an earlier stage

Reduced  activity of UROD leads to accumulation of  porphyrins (eg uroporphyrin) which can be transported to the skin.

These porphyrins are ‘photosensitizing’

-Sunlight (UVA and visible light ranges) cause them to become excited and damage surrounding tissue.

Clinical:

Sun sensitivity

Increasingly fragile skin on back of hands and forearms

Get multiple erosions and blisters

This heals with scarring in the form of milia (tiny cysts)

Can also get hyperpigmentation on face and neck and hypertrichosis (excess hair)

Diagnosis:

Skin biopsy: sub epidermal blistering

All porphyrias that cause skin lesions have elevated plasma porphyrins

Elevated urinary uroporphyrin (and others) and fecal porphyrins indicate PCT

[Should probably do iron studies, HIV and viral hepatitis testing in these patients]

(Urine may look reddish/‘tea’ coloured)

Avoid unnecessary exposure to strong light



 Looks like porphyria cutanea tarda

BUT porphyrin levels are normal

Reaction here is to UV light and not visible light like PCT

Symptoms:

Photosenstivity and fragility

Tense blisters at minor trauma sites (and erosions/scabs)

Often on hands and feet

Heal with scars and milia

Usually medications: (medications react with sunlight to cause photoxic reaction in skin)

·      NSAIDs

·      Antibiotics-doxycycline

·      Diuretics- thiazides, furosemide, bumetanide

·      Retinoids- acitretin, isotretinoin

·      OCP

Investigations:

Phototesting to confirm photoxic action of the supected agent

Skin biopsy of blister

May check porphyrins in blood, urine and faeces to rule out PCT

Management:

Withdraw offending agent (usually goes away in weeks but cn persist)

Sun protection

Variegate porphyria:

Due to protoporphyrinogen oxidase deficiency

Looks exactly like PCT in skin

Often presents earlier than PCT (teens)

Very important to diagnose as if misdiagnose can prove fatal

Variegate porphyria can cause acute, systemic internal attacks 

Acute porphyria signs/symptoms:

AIP, Variegate porphyria, hereditary coproporphyria

Can present with sudden life-threatening crisis

Most patients have one or only a few attacks followed by resolution of syndrome

Attacks occur rarely in childhood with incidence increasing after puberty

Manifest by neurovisceral symptoms and autonomic sequelae

Neuro: fatigue, confusion, seizures, motor neuropathy

GI: abdominal pain, N/V, constipation

Autonomic: hypertensive urgency, fever

Hyponatraemia

(Think in someone with unexplained neurological symptoms in someone with autonomic and/or GI symptoms and hyponatreaemia)