IRISH DERM TUTOR

Introduction

Differential diagnosis blistering rash

Diagnostic approach

Skin biopsy

• H&E

• DIF

• Salt split skin test

• Blood tests

  • Indirect immunoflourescence

  • ELISA

Pemphigus group:

• Epidemiology

• 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

The keratinocytes of the epidermis are held together by a family of proteins called the desmosomes

The basal keratinocytes are held to the basement membrane zone and the dermis below that via another family of proteins called the hemidesmosomes

In superficial blistering diseases (eg pemphigus vulgaris) the connection between the keratinocytes has been targeted

There are many proteins involved in keratinocyte adhesion and these collection of proteins are called desmosomes

If any of these are targeted 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 hemidesmosomes are the collection of proteins involved in keeping the basal keratinocytes attached to the extracellular matrix in the 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 (pemphigus diseases)

If the site of blistering occurs lower for instance around the dermo-epidermal junction the blisters will be much more tense (pemphigoid diseases and other subepidermal blistering diseases)

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

There is a long list of differential diagnoses when you see a blistering condition

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

The autoimmune blistering disorders are a group of disorders which occur due to antibodies directed against structural antigens

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 (+/- salt split skin test)

• Blood test for indirect immunoflourescence +/- ELISA (the latter can quantify the amount of circulating antibodies in the blood)

A biopsy should be taken of a lesional area containing a bit of blister but also the surrounding skin and this should be sent for H&E in the standard formalin pot (4mm punch biopsy is usually sufficient)

Another 4mm punch should be taken of peri-lesional normal skin (within 1cm of the active blister). Preferably the biopsy would be from non-inflammed skin. This biopsy should be sent in michel’s medium pot

H&E by itself can’t give you a full diagnosis but it can give you some clues to the diagnosis based on:

The level of the split -

• Subcorneal

• Intraepidermal

• Subepidermal

The nature of the inflammatory infiltrate:

• Neutrophils

• Eosinophils

• Lymphocytes

• Cell poor

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

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

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 often bind linearly to the DEJ

Can help differentiate bullous pemphigoid from other sub-epidermal blistering conditions such as epidermolysis bullosa acquisita and mucous membrane pemphigoid

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

In Bullous Pemphigoid the antibody (usually IgG) will be found on the blister roof (epidermal side of split skin)

In EBA the antibodies will be found on blister floor (dermal side of split skin)

In mucus membrane pemphigoid the deposition can be to the roof or floor or even a mixed picture depending on the antigens targeted

Blood tests can be performed for the serologic detection of antibodies
The conventional method performed is:

• 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 immunoflourescence (IIF) is very sensitive so it is good for screening purposes but not as specific for determiniation of the causative autoantibody as ELISA

IIF 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 of the suspected disease

For instance, classic prepared tissues which are better for certain diseases are:

• Sub-epidermal blistering diseases - Normal human skin

• Pemphigus vulgaris - monkey oesophagus - monkey oesophagus has high expression of Dsg 3 (think of monkey’s acting vulgar)

• 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

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 in my experience it seems to be the one that is usually used these days

It is based on 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 and is helpful in diagnosis and in disease activity monitoring)

The commonest ELISAS tested are for antibodies to the following:

• Dsg 1 and 3

• BP 180 and 230

• Collagen VII

Now can do panels where you can cover multiple antigens in one go and in some instances potentially can be used as a screening test instead of IIF

Pemphigus is a group of autoimmune bullous diseases primarily affecting the skin and/or mucous membranes

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 are desmoglein 1 and 3

In pemphigus these proteins can be targeted resulting in antibody-mediated acantholysis

• Acantholysis refers to the separation of keratinocytes due to the disruption of these intercellular bridges

Clinically this leads to the formation of fragile blisters and erosions

Desmoglein 1:

• Most abundant in the superficial layers (eg stratum granulosum/corneum) of the epidermis

• It is present in high concentrations in the skin.

• It is found in lower amounts in the mucosal tissues

Desmoglein 3:

• Most abundant in deeper layers (basal and lower spinous)

• It is highly abundant in the mucous membranes

• It is present in the deeper layers of the epidermis but at lower levels than Dsg1

The location of these desmogelins explains how the different types of pemphigus present

In pemphigus foliaceus you have antibodies directed against Dsg 1 and not Dsg 3 and the diseasse is predominantly cutaenous - think only 1 main antibody which targets only 1 main organ (skin)

In pemphigus vulgaris you will always have antibodies targeted against Dsg 3 +/- Dsg 1 and the disease usually affects the mucous membranes predominantly but the cutaneous features can still be very severe

In Europe, studies report 0.5 to 8 cases per million

Pemphigus vulgaris and foliaceous collectively account for 90-95% of all pemphigus cases

Pemphigus vulgaris is the most common form

In Brazil, there is an endemic form of pemphigus foliaceous which is also called ‘fogo selvagem’ which means wildfire in Portuguese which we will discuss later

Peak age of onset of pemphigus is typically between 40 and 60 year olds and it is rare in individuals under 20 years of age

It tends to be more common in females

There is a higher frequency of pemphigus in people of Jewish ancestry (partiularly Ashkenazi Jews)

Genetics:

• HLA alleles are strongly associated with an increased risk of pemphigus - th emost significant are DRB104:02 and DRQB105:03

Associated diseases:

Pemphigus patients may have increased frequency of -

• Haematological malignancy - CLL, NHL, Multiple myeloma

• Solid organ cancers - oropharyngeal, colon

• Autoimmune diseases - Thyroid, RA

Pemphigus foliaceus results from antibodies primarily directed against desmoglein 1

As Dsg1 is most abundant in the superficial layers of the epidermis and found in lower amounts in mucosal tissues, PF typically presents with predominantly cutaneous lesions and rare mucosal involvement

The split occurs very high in the epidermis, at the subcorneal or granular layer

Clinical features:

Classically presents with crusted erosions and shallow erosions, often in a seborrhoeic distribution (can sometimes resemble a seborrhoeic dermatitis)

Common affected areas include the scalp, central chest, face, and mid-back

Due to the superficial nature of the blistering, intact blisters are rarely observed; instead, they quickly rupture, leaving erosions

The erosions are generally less painful than those in pemphigus vulgaris, but they can cause itching or burning

PF can also be drug induced (NSAIDs, ACEi, nifedipine)

Skin biopsy:

Take a biopsy of a blistered area which includes intact surrounding skin for H&E

Take a biopsy of a peri-lesional area (within 1cm) for DIF

H&E:

Reveals a split in the upper layers of the epidermis (subcorneal/granular layer)

Can see acantholysis and spongiosis within the stratum granulosum extending into the stratum corneum

In the dermis there is a predominantly superficial lymphocytic infiltrate and may see scattered eosinophils

Neutrophils may be more common in IgA subtype of pemphigus

Pathological differential diagnosis intra-epidermal/sub-corneal split includes:

• Bullous impetigo

• Sub-corenal pustular dermatosis

• Staphylocccal scalded skin syndrome

Direct immunoflourescence:

Shows intercellular IgG with or without C3 deposition in the superficial layers of the epidermis epidermis, characteristic of the 'chicken wire’ or ‘fish net’ pattern

Indirect immunoflourescence:

While monkey oesphagus is commonly used, guinea pig oesophagus is often cited as a good substrate for detecting Dsg 1 antibodies

Again the chicken wire pattern is often seen

ELISA:

Desmoglein 1 antibodies high

Desmoglein 3 antibodies normal

Quantification of Dsg 1 titres can aid in monitoring disease activity

Subtype: Endemic Pemphigus (Fogo Selvagem)

Endemic pemphigus, also known as fogo selvagem (meaning 'wildfire' in Portuguese), is essentially an endemic form of pemphigus foliaceus in Brazil

This if thoguht to be environmentally induced possibly from inset bites (eg from black flies). Proteins left behind from the bite may induce immune mimicry leading to development of antibodies directed against the skin

The investigative findings (H&E, DIF, IIF and ELISA) are consistent with pempihigus foliaceous, showing antibodies against Dsg 1

Charaterised by antibodies against desmoglein 3 and/or desmoglein 1

The presence of anti-Dsg3 antibodies means mucosal involvement is common and often predominant, as Dsg3 is highly abundant in mucous membranes

When both anti-Dsg3 and anti-Dsg1 antibodies are present, patients tend to experience severe skin disease in addition to mucosal lesions

The acantholysis in PV occurs just above the basal layer of the epidermis, leading to a suprabasilar split

Clinical Features:

Patients typically present with shallow, fragile blisters that rupture easily, leading to erosions and crusting on both skin and mucous membranes.

The skin lesions can often initially appear on the scalp, face, and in a shawl-like distribution on the upper central torso.

At presentation oral involvement is present in about 50-70% of cases and with time this increases to 80-90% (with some series reporting 100%)

Patients can get oral erosions which can be painful with irregular borders and an erosive gingivitis

Laryngeal involvement can ccause a hoarse voice and requires urgent ENT review due to the potential for oedema and erosions in the areas

Ocular involvement can manifest as crusted erosions on the eyelid margins and conjunctiva with conjunctival erythema, injection and swelling

Painful erosions can also affects the genitalia and nasal mucosa

Skin biopsy:

Take a biopsy of a blistered area which includes intact surrounding skin for H&E

Take a biopsy of a peri-lesional area (within 1cm) for DIF

If have isolated oral disease or need a biopsy from oral tissue you generally need two biopsies

For H&E take from lesional tissue (ulcer/erosion) with some normal mucosa intact (formalin)

For DIF you can take it from normal buccal mucosa rather than peri-lesional areas which is usually sufficiently reliable


H&E:

Suprabasilar split (acantholysis) just above the basal layer of the epidermis

The basal keratinocytes lose contact with their neighbours but remain attached to the basement membrane, giving a characteristic 'row of tombstones' appearance

The inflammatory infiltrate may contain eosinophils and neutrophils

Direct immunoflourescence (DIF):

Demonstrates granular or linear IgG and/or C3 deposition at the surface of epidermal keratinocytes, creating a distinctive 'chicken wire pattern

DIF alone cannot differentiate PV from pemphigus foliaceus

Indirect immunoflourescence (IIF):

Clasically performed on monkey oesophagus (rich in Dsg 3) or can be done on normal human skin

Chicken wire pattern again observed

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

ELISA:

Can identify the specific antibodies to Dsg 3 +/- Dsg 1 and quantify them bloods

If anti-Dsg 3 is positive it is considered pemphigus vulgaris

Anti-Dsg 3 antibody levels can to some degree be correlated with severity of oral disease and anti-Dsg 1 with skin severity

Can use ELISA to help monitor disease activity and predict remission

Paraneoplastic pemphigus is a rare but severe form of pemphigus with a poor prognosis

It is due to an abnormal B or T cell immne respoonse to an underlying malignancy

It is distinguished by antibodies to a wide range of epitopes, including desmoglein 3, desmoglein 1, envoplakin, periplakin, and desmoplakins, among others

Cytotoxic CD8 T cells also play a role which can lead to an interface dermatitis seen alongside acantholysis

This broad range of antibody targets and the cytotoxic T cell role contributes to the polymorphic clinical presentation we often see

Clinical features:

Patients often unwell

Typically begins with painful oral erosions, which can progress to severe and recalcitrant ulceration with pan-stomatitis and hyperplastic mucosa

Haemorrhagic cheilitis (crusted, bleeding lips) and severe ulceration in the oropharynx and genitalia are characteristic and often out of proportion to cutaneous involvement

The rash is often polymorphic with a variety of lesions and it can mimic other conditions like erythema multiforme, lichen planus or GVHD

Other organs can be affected:

• Lung involvement can lead to bronchiolitis obliterans (which can be severe)

• GI tract can be involved

Associated cancers:

• Lymphoma ≈ 40% of cases

• CLL ≈ 30%

• Castleman’s disease ≈ 10%

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

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

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

• Thymoma ≈ 6%

• Spindle cell neoplasms ≈ 6%

• Waldenstrom’s macroglobulinaemia ≈ 6%

Histology:

Can have mulitple processes seen within the specimen:

• Suprabasal or full-thickness acantholysis which can be more irregular and extensive than typical pemphigus

• Lichenoid/interface dermatitis with basaal vacuolation and band-like lymphoplasmacytic infiltrate

• Many scattered dyskeratotic/necrotic keratinocytes scattered throughout the epidermis,mimicking Erythema Mulitforme

The coexistence of pemphigus-type acantholysis with a lichenoid/interface pattern is the key H&E pointer to paraneoplastic pemphigus

Pemphigus vegetans is a rare variant of pemphigus vulgaris (approx 2% of cases) which is chracterised by its clinical presentation rather than distinct antibody profiles

Clinically patients get vegetating, hyperkeratotic, papillomatous and fissured erosions
It typically affects flexural areas such as the axilla, groin and under the abdomen

They are often bacterial colonised and malodorous

Oral lesions are common and patients can get a distinctive cerebriform tongue

H&E: Histology may show eosinophilic abscesses or spongiosis with few acantholytic cells, which might not immediately look like typical pemphigus

DIF: Shows characteristic intercellular depoisition of IgG (chickenwire)

IIF: ELISA shows antibodies against Dsg 3 and desmocollins

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)