Cutaneous small vessel vasculitis (CSVV) refers to a vasculitis involving primarily dermal post-capillary venules and when a biopsy is taken you see a specific histological pattern of vasculitis called leucocytoclastic vasculitis (LCV)

In LCV the postcapillary venules of the dermis are affected by an intense neutrophilic vascular inflammation

LCV often used interchangeably with CSSV but LCV however:

LCV can be seen in settings of mixed small and medicum vessel vasculidities (eg Granulmatosis with polyangiitis) whereas the term CSVV should generally be reserved for when only small vessels are involved (without any mixed sized vessel involvement)

Leucocytoclastic vasculitis on biopsy:

Neutrophils around blood vessels
Leucocytoclasis (degnerating neutrophils) forming ‘nuclea dust’
Fibrinoid necrosis (within vessel wall, looks pink)
Extravasated red cells

Small and medium vessel vasculidities tend to be either an immune complex mediated vasculitis or an ANCA associated vasculitis

Immune complex mediated vasculitis pathology:

All forms of CSVV and some forms of mixed and medium-sized vessel vasculidities are mediated by immune complexes (type 3 hypersensitivity reaction)

Essentially an antigen (eg a virus) is bound by antibodies and forms immune complexes

These deposit into postcapillary venules in the skin

These lodged complexes then activate complement which attracts neutrophils which damage the blood vessels allowing red blood cells to leak out

ANCA associated vasculitis pathology:

The ANCA associated vasculidities are not mediated by immune complexes

PR3 and MPO are intrecellular neutrophillic proteins that can translocate to the neutrophil cell surface after activation by cytokines (eg TNFα)

An ANCA antibody can then bind to these antigens resulting in adhesion of neutrophils to the blood vessel endothelium

This results in release of inflammatory mediators, vessel damage and recruitment of additional inflammatory cells

As there is a lack of immune complex deposition on immunoflourescence we call this pauci-immune

CLINICAL APPEARANCE (based on size of vessel affected)

Small Vessels:

Arterioles, capillaires, postcapillary venules

Superficial and mid dermis

Skin manifestations:

Palpable purpura
- If gently feel around area, it will feel raised
- Non-blanching
Macular purpura
Petechiae
Urticarial papules
Vesicles
Pustules
Targetoid papules and plaques

Palpable purpuraCourtesy Dr. Mccoll — **Palpable purpura**
Courtesy Dr. Mccoll

Medium Vessels:

Small arteries and veins

Deep dermis and subcutis

Skin manifestations:

Livedo racemosa
Retiform purpura
Ulcer
Subcutaneous nodules
Digital necrosis

So can get a patient with manifestations of:

Small vessel signs only

Medium vessel signs only

Combination of both

CLASSIFICATION

Clinically (+/- histologically) should give consideration to what size of vessels are affected as this may give a clue to the underlying cause

Classification by size (Chapel Hill classification)

Small vessels:

Idiopathic cutaneous small vessel vasculitis
Secondary cause of cutaneous small vessel vasculitis
- Drugs
- Infection
- Malignancy (usuallly haematologic)
Urticarial vasculitis
Henoch-schonlein purpura
Acute haemorrhagic oedema of infancy
Erythema elevatum diutinum

Small and medium vessels:

Cryogloulinaemia (Type II and III)
ANCA-associated
- Microscopic polyangiitis (MPA)
- Wegener’s granulomatosis (GPA)
- Churg-Strauss (EGPA)
Secondary causes
- Infection
- Inflammatory disorder (eg autoimmune connective tissue disease)

Medium sized vessels:

Poyarteritis nodosa (PAN)
- Classic (systemic) PAN
- Cutaneous PAN

Large sized vessels:

Temporal arteritis
Takayasu’s arteritis

Other considerations when classifying cutaneous vasculitis:

Look for underlying causes

? ANCA positive or negative
Direct immunoflouroescence findings: Especially ? IgA predominance
Evidence of systemic manifestations

REVIEW OF SYSTEMS

If there is concerns about a systemic vasculitis a thorough review of systems should be performed in history for past and present symptoms.

Constitutional: Fever, weight loss, night sweats, arthralgias
URTI
- Oral/nasal ulcers
- Nasal perforation, saddle nose deformity
- Sinusitis
- Hearing loss/recurrent otitis media
- Change in voice (vocal cords)
- Subglottic stenosis
Eyes
- Psueotumours
- Conjunctivitis
LRTI (lung infiltrates, cavities, haemorrhage)
- Can be sudden and acute or chronic
- Shortness of breath, cough haemoptysis, pleuritis
Cardiac (myocarditis/pericarditis)
- Chest pain, shortness of breath, palpitations
GIT:
- Abdominal pain
- Change in bowel habits
- Blood pr
Kidneys: (Glomerulonephritis, vascular occlusion)
- Urine dipstick blood, protein, casts
- Urine Protein:creatinine ratio
Peripheral neuropathy
- Motor (eg foot drop)
- Sensory
CNS changes
- Stroke like symptoms
Skin changes
- Palpable purpura
- Livedo reticularis
- Nodules
- Ulceration
- Necrosis

VASCULITIC SCREEN

When assessing for a vasculitis it is important to look for any kidney damage and is essential to check and monitor blood pressure and perform a a urine dipstick

If the urine dipstick shows protein and/or blood it is important to send for urinary protein:creatinine ratio

Also may perform ‘vasculitic screen’, an example of a vasculitic screen that could be considered would be:

FBC
U&E/LFT
CRP/ESR
Antibodies: ANA, ENA, dsDNA, RF
Anti-neutrophil cytoplasm antibodies (ANCA)
Complement levels
Cryoglobulins
Hepatitis B/C, HIV serology
Immunoglobulins
Serum electrophoresis
Anti-streptocccal titre (ASOT)
Skin biopsy with samples sent for H&E and direct immunofluorescence (DIF)
- Ideally performed in first 24-48 hours
- DIF:
  - +ve in 80% CSVV
  - +ve 100% lesions < 24 hours old
  - +ve 30% at 48-72 hours
  - Only C3 > 72 hours
  - Granular pattern within vessel wall
  - C3, IGM, IgA +/- IgG
  - Negative in ANCA associated vasculitis

CUTANEOUS SMALL VESSEL VASCULITIS (CSVV)

As mentioned previously it involves primarily dermal post-capillary venules and it is charachterised histologically by a leucocytocastic vasculitis

The term CSVV is generally reserved only for when small vessels are involved (without medium sized vessel involvement )

Causes:

Idiopathic (45-55%)
Infection (15-20%)
- Bacterial - Group A strep
- Viral - Hepatitis B/C, HIV
- Fungal - Candida
Inflammatory (15-20%)
- Autoimmune onnective tissue disease: RA, SLE, Sjogen’s
- IBD
- Seronegative spoindylarthropathy
Drug (10-15%) (following list not exhaustive)
- Anti-inflammatories:
  - NSAIDs
  - COX-2 inhbitors
- Antibiotics:
  - Beta lactam antibiotics
  - Trimethoprim/sulfamethoxazole
  - Quinolones
  - Vancomycin
- Allopurinol
- Cardiac medications
  - Diuretics: thiazides, loop
  - ACEi, beta blockers
- OCP

Neoplasm (5%)
- Often haematological but can be due to solid organ cancers also

Within the spectrum of CSVV there are several subtypes with unique features:

Henoch schonlein pruprua
Acute haemorrhagic oedema of infancy
Urticarial vasculitis
Erythema elevatum diutinum

CSVV clinical features:

Typically present 1-2 weeks after exposure to inciting agent

Usually presents with palpable purpura and petechiae on dependant areas such as the lower legs and pressure points

Can also present as:

Urticarial lesion
Vesicles
Pustules
Targetoid lesions

Lesions often more severe in areas under pressure (eg sock line)

Can be itchy +/- painful

Residual postinlfammatory hyperpigmentation may persist for months after primary process resolves

Extracutaneous involvement can occur (eg fever/arthralgias, gastrointestinal or genitourinary involvement) but is uncommon and usually mild

Prognosis:

90% will have spontaneous resolution of cutaneous lesions within weeks/few moths

10% will have chronic or recurrent disease at intervals of months to years

Assessment:

Determine if patient has particular sub-type of CSVV (eg HSP)

Outrule a systemic vasculitis syndrome

Consider secondary causes

Treatment:

It often resolves without any treatment

Remove inciting trigger
Supportive measures:
- Leg elevation, avoid tight clothing, rest
Symptomatic therapy:
- Antihistamines, NSAIDs

Chronic disease (> 4 weeks) or more severe cutaneous disease consider:

Colchicine 0.6mg bd-tds (often get GI side effects)
Dapsone 50-200mg/day
Can consider both in combination

Severe, ulcerating or progressive cutaneous disease needing rapid control:

Short course of systemic oral steroids
- Up to 1mg/kg/day
- Taper over 4-6 weeks
If recurs when dose is tapered or disease is recalcitrant may need steroid sparing agent
- Methotrexate
- Azathioprine

HENOCH SCHONLEIN PURPURA

HSP is an IgA vasculitis (IgA predominance seen on immunoflourescence)

It is the commonest form of vasculitis in children

(90% occur in children < 10 years)

Children classically initially have a URTI or strep infection

1-2 weeks later symptoms and signs

Evidence of medium vessel disease or widespread lesions (including face) could indicate an underlying IgA paraproteinaemia

HSP tetrad:

1. Palpable purpura legs and buttock

2. Arthralgia of knees and ankles

3. GI issues including abdominal pain and diarrhoea with or without melena

4. Renal changes with haematuria, possible nephritis and rarely renal failure (1% of cases)

HSP clinical findings:

Cutaneous findings:

Erythematous papues/plaques evolving to palpable purpura is classical finding
Urticaria, vesicles, bullae and foci of necrosis can be seen
Typically symmetrical and distributed on buttocks and lower extremities
Can involve trunk, upper extremities, face
Individual lesions last 10-14 days with skin resolution over weeks-months
Can get recurrent skin disease in 5-10% of patients

Arthritis:

Up to 75% of patients
Commonly joints of lower extremities (knees and ankles)

Gastrointestinal::

50-75% of patients
May precede purpura
Colicky abdominal pain
Vomiting
GI bleeding (30%)
Rarely - intussusception and bowel perforation

Renal:

40-50% of patients
Microscopic haematuria (40$)
Proteinuria (25%)
Cutaneous lesions often precede nephritis but latter usually clinically evident within 3 months
Persistent renal disease (requiring monitoring till resolution) in 30-50% of patients
Only 1-3% of children develop long-term renal impairment

Orchitis:

Can rarely occur in young boys

Poor prognostic features HSP:

Renal failure at time of onset

Nephrotic syndrome

Hypertension

IgA small vessel vasculitis adults (sometimes called adult HSP)

Clinical presentation and prognosis differ to children

Necrotic skin lesions present in 60% of adults (vs <5% children)

Up to 30% may develop chronic renal insufficiency

3 findings suggestive that an adult with HSP will have kidney involvement with a IgA glomerulonephritis:

1. Fevers

2. Increased ESR

3. Purpura located above the waist (‘think purpura getting close to kidneys so more likely to be involved’)

Adults more likely to require more aggressive therapy

If IgA vasculitis due to cancer 60-90% is due to solid organ cancer (particularly lung)

This is in contrast to most CSSV in which cancer is usually haematologic

Diagnosis:

Biopsy: leucocytoclastic vasculitis

DIF: IgA deposition in blood vessel walls so many people recommend to do biopsies in rashes suspicious for vasculitis as it will give an indication if we need to monitor for renal disease as time goes by

(IgA can be seen in other types of CSSV so diagnosis of HSP supported by IgA predominance)

Monitoring:

Serial urinalysis (+/- urine pcr)

Check faecal occult blood if have GI symptoms

Treatment:

Disease usually self-limited and resolves over weeks to months

Supportive
Dapsone or colchicine may decrease duration of cutaneous lesions
Systemic steroids can treat the arthritis, the abdominal pain and duration of skin lesions (but do not prevent skin recurrence)
Refer to nephrology if evidence of renal involvement as treatment
- They could consider ACEi, steroids or other treatments

URTICARIAL VASCULITIS

Clinical presentation resembling urticaria but see LCV on histopathology

Often idiopathic but can be associated with:

Autoimmune connective tissue disease: SLE, Sjogren’s, RA
Infections - HBV, HCV, EBV
Serum sickness
Medications - NSAIDs, fluoxetine, potassium iodide
Malignancies - usually haematological

Cutaneous features:

Unique from regular urticaria in that:

1. Urticarial papules and plaques last > 24 hours

2. More pain and burning than itch

3. May have residual haemorrhage

4. May esolve with postinflammatory hyperpigmentation

5. May have systemic symptoms (See below)

Rarely presents as: Bullae, EM like lesions, Livedo reticularis

Can be associated with or without angioedema

Urticarial vasculitis further broken down in to:

Normocomplementaemic (3/4 of cases)
- Mostly skin limited
- Average duration 3 years
Hypocomplementaemiac (1/4 of cases)

Hypocomplementaemic urticarial vasculitis is more likely to be associated with systemic changes with the following systems involved:

Arthralgia
- Of hands, elbows, knees and ankles in 50% of patients with urticarial vasculitis
- 50% of patients with HUVS (see below) have frank arthritis
Pulmonary
- Up to 20% have pulmonary symptoms - cough, laryngeal oedema, haemoptysis, asthma, COPD
- The COPD is especially severe in smokers with urticarial vasculitis
GI
- 30% of patients
- Abdominal pain, nausea, vomiting, diarrhoea
Renal
- 5-10% of patients with HUVS
- Look for proteinuria/haematuria
Ocular
- Uveitis/episcleritis occurs in HUVS

Hypocomplementaemic urticarial vasculitis syndrome (HUVS) is a more severe syndrome defined by specifc diagnostic criteria:

Patients with hypocomplementaemia who don’t meet the above criteria have hypocomplementaemic urticarial vasculitis but not HUVS

They are not thought to transition from one to another

Common abnormal labs urticarial vasculitis:

High ESR
Low C3, C4 and CH50 (this is decreased if components of classical complement pathway are low)

HUVS marked by:

Low serum complement
Plus presence of anti-C1q antibody and low C1q levels

HUVS and SLE:

HUVS can share features with SLE

Distinctive clinical findings in HUVS are:

Ocular inflammation (30%) - conjunctivitis, episcleritis, iritis,uveitis
Angioedema (>50%)
COPD like symptoms (50%)

Lab findings HUVS and SLE:

1/3 patients with SLE have anti-C1q antibodies
Up to 1/2 patients with HUVs have positive ANa
But patients with HUVS rarely have anti-dsDNA or anti-Sm antibodies

Diagnosis urticrial vasculitis:

H&E:

Finding of leucocytoclastic vasculitis is essential for diagnosis of urticarial vasculitis

(can often be subtle)

DIF:

70% Immunoglobulin, C3 or fibrin around blood vessels

Can see granular pattern along basement membrane in 80% of lesions - if this is accompanied by hypocomplementaemia this may be suggestive of a diagnosis of SLE

Treatment:

No RCTs

Antihistamines may reduce swelling and pain associated with lesions but do not alter course

Considerations:

Oral steroids effective but keep duration to a minimum
NSAIDs: indocmethacin
Dapsone
Colchicine
Hydroxychloroquine
MMF
Rituximab or IVIG may also be useful for recalcitrant hypocomplementaemic urticarial vasculitis

Schnitzler’s syndrome:

• Urticarial vasculitis

• Monoclonal IgM gammopathy

and at least two of the following:

Fever (periodic)
Arthralgia
Hepatosplenomegaly
Increased ESR
Increased WBC
Bone abnormality
Bone pain
Resolve with postinflammatory hyperpigmentation

Cryoglobulinaeimas:

Cryoglobulins are immunoglobulins that precipitate in the cold

Cryoglobulinaemia broken down in to 3 types:

Type 1:

Doesn’t cause a vasculitis

Usually due to monoclonal IgM (Less frequent IgG which is > than IgA)

Symptoms and signs due to ‘sludging’ of the blood vessels with microvascular occlusion

◦ Associated with plasma cell dyscrasias and lymphoproliferative disorders

◦ Present with:

‣ Livedo reticularis

‣ Raynaud’s

‣ Acrocyanosis

‣ Retiform Purpura

Type 2 and 3 - ‘mixed cyroglobulinaemias’

Approx 15% of patients with circulating mixed cryoglobulins present with symptoms due to cryoblobuniaemic vasculitis

Antibodies combine to form immune complexes which deposit in the blood vessels which activates complement causing a leucocytoclastic vasculitis

Causes a vasculitis that can involve both small and medium-sized vessels (preferentially small)

It typically affects:

Skin
Peripheral nervous system
Kidneys

Type 2 cryoglobulinaemias exhibit monoclonal IgM or IgG directed against polyclonal IgG

Type 3 cryobloulinaemia exhibit polyclonal IgM against polyclonal IgG

Occurs in setting of -

Infections:

Hepatitis C virus accounds for 70-90% of cases
- >50% of patients with HCV infection have cryoglobulinaemia
- Overt cryogloublinaemic vasculiltis develops in approx 5% of these cases
- Higher prevalence in Southern Europe as increased prevalence HCV here
Hepatitis B virus (5% of cases)
EBV, CMV, Leishmania, Trepenoma

2. Connective tissue diease:

RA
Sjogrens
Systemic sclerosis

3. Lymphoproliferative disorder (5%)

B-cell non-hodgkin lymphoma
CLL
Macroglobulinaemia
Rarer: solid tumours (HCC)

Clinical cryoglobulinaemic vasculitis:

Cutaneous:
- Commonest to have palpable purpura of lower extremities
- Can see ecchymoses and dermal nodules
- Rarer: urticaria, livedoe reticularis, necrosis, ulceration, bullae
- Not typically cold induced (in contrast to vascular occlusive lesions in type 1 cryoglobulinaemia)
Arthritis - 70%
Peripheral neuropathy - 40% (typically sensory)
GI disease or hepatitis - 25%
Rarer:
- Xerostomia/xerophthalmia
- Endocrine issues (thyroid/gonads)

Investigations:

Elevated cryoglobulins
- Can be falsely negative
- Need to check during clinical flares and on more than one occasion
- Blood sample should be kept warm at 37°C until it is spun in the lab to avoid a false negative
- Check with lab their protocol prior to collecting cryoglobulins
Rheumatoid factor - is positive in 70-90% cases
- Is an easier test to perform than cryogloublins
- RF by definition is an autoantibody against the Fc portion of IgG
- Fc portion is the bottom of the Y shape of the antibody
- Types 2 and 3 mixed cryobloulinaemias consist of immune complexes containing antibodies to IgG so you often get positive RF
ANA - 20% positive
Complement - often low or undetectable C4
SPEP - 15% with mixed cryoglobulins have monoclonal gammopathy
Hepatitis and HIV serology

Pathology:

H&E:

Leucocytoclastic vasculitis

DIF:

Granular deposits of predominantly IgM and C3 in a vascular pattern observed in papillary dermis

Treatment:

Treat hepatitis C infection
- Interferonα pluse ribavirin often can lead to resolution of cutaneous (100%), renal (50%) and neurological manifestations
- I rare cases interferon can make the peripheral neuropathy worse

Considerations if severe:

Plasma exchange
Cyclophosphamide
Rituximab

ANCA associated vasculitis

Granulomatosis with polyangiitis (Wegener’s granulomatosis)

Microscopic polyangiitis
Eosinophilic granulomatosis with polyangiitis (Churg Strauss)

Together these conditions have annual incidence of 20 cases per million people in N. America and Europe

Anti-neutrophil cytoplasmic antibodies (ANCA) refer to IgG auto-antibodies that target antigens in the cytoplasm of neutrophils (mostly) and monocytes

To improve specificity two tests are usually done on a patients blood:

Indirect immunoflourescence on a patient’s neutrophils can demonstrate two vasculitis relevant patterns of staining:
- cytoplasmic: c-ANCA
- perinuclear: pANCA
ELISA which can specifically detect antibodies to the relevant antigens
- Proteinase 3 - anti-PR3 antibodies
- Myeloperoxidase - anti-MPO antibodies
- ELISA can detect the amount of antibody present as a titre
- The higher the titre, the more antibody there is (ie 1:64 > 1:8)

About 85% of patients with cANCA pattern have PR3 antibodies

About 90% of patients with pANCA pattern have MPO antibodies

Often do IIF first which detects pANCA or cANCA staining and if positive you then do ELISA to specifically detect anti-PR3 antibodes or anti-MPO antibodies

However, up to 5% of serum samples are positive for ELISA only so if there is a high index of suspicion for ANCA associated vasculitis should perform ELISA even if IIF is negative

Anti-PR3 ANCA:

+ve in up to 90% of patients with GPA (Wegener’s)
+ve in 30% of patients with MPA

Anti-MPO ANCA:

+ve in 60% of patients with MPA
+ve in 60% of patients with EGPA (Churg-Strauss)

Can use ANCA for disease monitoring and also for checking response to treatment

Presence of ANCA within first year following remission has been associated with disease relapse

Pathogenesis:

PR3 and MPO are intrecellular neutrophillic proteins that can translocate to the neutrophil cell surface after activation by cytokines (eg TNFα)

An ANCA antibody can then bind to these antigens resulting in adhesion of neutrophils to the blood vessel endothelium

This results in release of inflammatory mediators, vessel damage and recruitment of additional inflammatory cells

As there is a lack of immune complex deposition on immunoflourescence we call this pauci-immune

Prognosis:

Morbiditiy and mortality of ANCA-associated vasculidities are relatively high due to:

Systemic manifestations disease
Complications of immunosuppressive therapy

Poor prognostic factors:

Delay in diagnosis
Renal impairment
Propensity for relapse
Older age
Presence of ANCA

Workup for systemic vasculitis:

Do extensive history for past and present clinical features (including)

Once a diagnosis is made the severity of the disease should then be assessed

Is it limited: eg chronic ENT disease
Is it severe (organ or life threatening): renal, pulmonary or neurological disease

Treatment is aimed at:

Remission induction
- To switch off the vasculitis activity
- Done over a course of 3-6 months
Remission maintenance
- To keep disease under control

The treatments for the various ANCA vasculidities in general are quite similar

GRANULOMATOSIS WITH POLYANGIITIS (formerly Wegener's granulomatosis)

Chronic systemic vasculitis

Small and medium sized arteries affected

Classic triad of symptoms for granulomatosis with polyangiitis:

1. Upper respiratory disease

2. Lower respiratory disease

3. Renal disease

Clinical findings:

Peak incidence age 30-50

Can involve multiple organ systems

MICROSCOPIC POLYANGIITIS

Can have quite similar clinical findings to GPA but without:

The granulomas
The upper respiratory findings

The progressive clinical course of MPA typically leads to renal failure and/or pulmonary haemorrhage

Antibodies:

Anti-MPO antibodies +ve 60% of patients
Anti-PR3 antibodies +ve 30% of patients

Skin biopsy:

Segmental necrotising vasculitis of small blood vessels and to lesser extent medium-sized arteries

No evidence of granulomatous inflammation

Treatment:

2 phases:

Induction of remission

Maintenance therapy

Induction remission:

Steroids initially (1mg/kg/day pred)
Addition of cyclophsphamide with significant organ involvement (renal, pulmonary, neurologic)
Can give cyclophosphamide for 6 months (orally 2mg/kg/day or IV Pulses 0.5-1g/m2/month)
Pulse therapy reduces total drug dose and incidence of side effects (eg bladder cancer)

Recent data suggest corticosteroids plus rituximab may be equally effective as steroids/cyclophosphamide

Maintenance of remission:

Methotrexate
Azathioprine
MMF
IVIG
Plasma exchange can be considered in ANCA-positive patients
Biologics (eg infliximab) has shown promise but further evidence required

Prognosis:

Higher rate of relapse compared to classic PAN (regardless of severity)

Lower rate than those with Wegener’s

Persistence of ANCA despite induction of remission associated with increased risk of relapse

EOSINOPHLIC GRANULTOMATOSIS WITH POLYANGIITIS (formerly Churg-Strauss syndrome)

Granulomatous small vessel vasculitis affecting mainly blood vessels of:

Lungs (severe asthma, allergic rhinitis)
GI tract
Peripheral nerves
Lesser extent:
- Skin
- Heart (leading cause of death)

3 phases:

1st phase - symptoms of allergic rhinitis, nasal polyps and asthma persisting for years

2nd phase - peripheral eosinphilia, respiratory tract infections, GI symptoms

3rd phase - Systemic necrotizing vasculitis with granulomatous inflamamtion which can occur several years to decades after initial symptoms

Investigations:

Elevated IgE
p-ANCA
Anti-myeloperoxidase +ve in 60%

POLYARTERITIS NODOSA

Necrotising vasculitis of medium sized muscular arteries

Comes in 2 presentations:

1. Classic systemic form

2. Cutaneous PAN (limited systemic involvement)

PAN can affect multiple organs but tends to spare one organ: the lung

Clinical:

Skin changes:

Palpable purpura lower legs
Painful subcut nodules following course of blood vessels
Lacy livedo reticularis interspersed amongst these purpura and nodules

PAN can affect multiple organs but tends to spare one organ - the lung

Kidney damage is due to issues with perfusion

Don’t get a glomerulonephritis in PAN

PAN associations:

• Hepatitis B > C

• HIV

• CMV

• Streptococcal infections

• IBD

Diagnosis (systemic PAN)

3 out of 10 criteria put out by ACR

Think of signs and symptoms first and then workup:

Investigations:

Blood pressure
Urinalysis

FBC (anaemia)
U&E
LFT
ESR/CRP
Hepatitis and HIV serology
ANCA (should be negative)
ASOT

Biopsy findings PAN:

LCV along with the arteritis of medium sized arterieis in the deep dermis and subcut tissue

May see a lobular panniculitis next to the involved vessels

Imaging:

• Renal angiogram to look for aneurysms or renal artery stenosis

Treatment:

• Immunosuppression:

◦ Systemic steroid for at least 6 months along with MTX or cyclophosphamide

• Organ specific management should involve other consultants (eg cardiology, nephrology)

• Treat any underlying causes (eg strep and Hep B)

KAWASAKI DISEASE

An acute febrile illness with vasculitis affecting the small and medium-sized vessels throughout the body, in particular the coronary arteries

Diagnostic criteria:

• Need fever of at least 5 days

and 4 out of 5 of other diagnostic criteria (Think CRASH and BURN)

• Burn= burning hot fevers > 39 celsius for five more days

Then four out of five of:

Conjunctivitis
Rash: polymorphous exanthem which can be peri-anal
Adenopathy: Cervical lymphadenopathy
Strawberry tongue or other oral changes
Hands/feet: erythema, oedema, eventual desqumation

Can also have:

Irritability, malaise, arthralgias
Uveitis
Gastroenteritis
Urethritis that may be symptomatic

Most cases are in children less than 5 years old

Especially around 10 months of age

Most patients have asian ancestry, especially Japanese kids

Coronary artery aneurysms can occur several weeks after symptom onset in about 25% of untreated children

These aneurysms are due to a medium vessel vasculitis

Lab investigation suspected Kawasaki disease:

FBC: WCC elevated, anaemia, thrombocytosis or thrombocytopaenia

U&E

LFT: Hypoalbuminaemia
CRP/ESR elevation
Nasal and throat swab looking for streptococcus
ASOT (As children with scarlet fever can have similar findings with fever, exanthem and strawberry tongue)
Blood culture
Urinalysis
Urgent ECHO looking for cardiac invovlement

Treatment:

Acutely ill:

IVIG 2g/kg over 12 hours as a single dose
- Check IgA levels before to outrule IgA deficiency
- If give IVIG to IgA deficienct patient they will see the IgA in IVIG as foreign and mount an immune reponse to it that can lead to anaphylaxis
High dose aspirin: 80-100mg/kg/day
- This is the only time aspirin is acceptable to give to children

If patients fail to respond to IVIG and aspirin they may need:

Repeat IVIG treatment
Corticosteroids
Steroid sparing agents (ciclosporin or cyclophosphamide)

Behcet's disease

Inflammatory disease charachterized by recurrent oral apthous ulcers and numerous potential systemic manifestations
Many, but not all, clinical manifestations of Bechet disease are believed to be due to vasculitis
Among the systemic vasculitides, Behcets disease remarkable for ability to involve blood vessels of all sizes (small, medium and large) on both the arterial and venous sides of the circulation

Epidemiology:

Generally equal sex ratio
Affects young adults (20-40)
More common (and often more severe) along the ancient silk road from Eastern Asia to Mediterranean
Highest prevalence in Turkey (80-370 cases per 100,000)
US/Northern Europe (0.12-7.5 per 100,000)
Close relationship in geographic distribution of HLA-B51 and prevalence of BD
Odds ratio of developing BD with HLA-B51 +ve: 5.78

Aetiology and pathogenesis:

Underlying cause of Behcet syndrome unknown
As with other autoimmune diseases:
- May represent aberrant immune activity triggered by exposure to an agent, perhaps infectious, in patients with a genetic predisposition to the disease
Genetic: HLA genes
Environmental influences: ? Abnormal immune response to microbes (eg Streptococcus or H pylori)

Clinical:

Mucocutaneous

Oral apthous ulcers

Painful, frequent, extensive

Urogential ulcers

Most specific lesion, less frequent, scar

Cutaneous (up to 75% of patients)

Acneiform lesions

Erythema nodosum

Pyoderma gangrenosum

Ocular (25-75%)

Anterior/posterior/pan uveitis

Retinal vasculitis

Optic neuritis

Neurologic disease (<10%, late onset, highly variable)

Parenchymal disease (brainstem, cerebrum, spinal cord)- wide range symptoms/signs

Non-parenchymal disease (meningism, cerebral venous thrombosis)

Vascular disease

Pulmonary artery aneurysm (Mortality approximately 25%) and thrombosis

Venous thrombosis (DVT, Budd-Chiari, Dural sinus thrombosis, SVC/IVC thrombosis)

Estimated 14-fold increased risk of venous thrombosis compared to controls

Arthritis

Non-erosive, aysmmetric, usually non-deforming

Gastro-intestinal

Abdominal pain, diarrhoea, bleeding (similar to IBD)

Renal and cardiac involvement

Infrequent but can occur

Pathergy:

Associated with Behcet’s disease

Is the development of cutaneous papulopustular lesions 24 hours after cutaneous trauma

More frequently positive in Behcet’s disease patients from endemic areas (50-75%) then non-endemic areas such as the US (10-20%)

Causes pathergy: Behcet’s, Pyoderma gangrenosum, Sweet’s syndrome

Diagnosis:

Behcet syndrome is best diagnosed in the context of recurrent apthous ulcerations along with characteristic systemic manifestations

There are no pathognomonic laboratory tests

Therefore diagnosis is made on the basis of clinical findings

Multiple diagnostic criteria exist:

One such example is the International Study Group Diagnostic Criteria (1990)

Another example is the International Criteria for Behcet’s Disease (ICBD, 2006)

Each of several findings are assigned a point value

Require at least 3 for diagnosis of Behcet’s