Approach to the

management of Cutaneous

Vasculitis Dr Deepshikha Khanna

Senior Resident

UCMS & GTB Hospital,

Delhi

What is vasculitis?

Inflammation of vessel wall

Presents as heterogenous mix of clinical syndromes

Clinical picture depends on

Size and extent of vessel wall

Organ system involved

Varied and overlapping clinical features

Difficulty in obtaining tissues

Difficult to diagnose and classify

Classification

Size of vessel wall – small/medium/large

American College of Rheumatology Criteria

Clinical, historical & histological divisions

Chappell Hill Conference (CHC) –histopathological findings

Etiological classification – primary / secondary

Cutaneous only / cutaneous with systemic involvement

Primary cutaneous vasculitis

Etiology

Idiopathic (45-55%)

Infection (15-20%)

Drugs, vaccines,

chemicals, allergies (10-

15%

Neoplasm (5%)

Connective tissue & other inflammatory diseases (15-

20%)

When to suspect?

Dependent palpable purpura

Livido reticularis

Punched out ulcers

Subcutaneous nodules

Bullae, necrosis & ulceration

Over dependent / pressure areas / trauma prone sites

Single / recurrent crops, resolving over 3-4 wks

Leaving ecchymotic stains / hyperpigmentation

In the absence of cutaneous findings, suspect if:

Ischemic S/S

Multi-system inflammatory disease

Fever & constitutional symptoms

Look for systemic involvement – Why?

May suggest exact type of vasculitis

Will guide diagnostic approach

Determine treatment protocol

Prognosis and follow-up

Ask for

Duration of complaints

drugs / exposure to chemicals /

food allergies/travel

H/o CTD / malignancy / sepsis

Constitutional symptoms

Hemoptysis, dyspnoea, cough, wheezing

Eye / ear symptoms, sinusitis

Numbness and paresthesias

Abdominal colic, malena, hematuria,liver dysfunction

Look for

Cutaneous findings

Morphological type

Size of vessel involved

BP, peripheral pulses

Neurological examination

Central / peripheral

Diffuse / focal

Pleural effusion / pleuritis

Pericardial effusion

Musculoskeletal system

Vessel sizes and clinical presentation

•Palpable purpura

•Splinter Hmg

•Urticaria

•Vesicles

•Ulcers

•Digital infarcts

•Nodules

•Livedo

•Necrosis

•Gangrene in an extremity

•Hypertension

•Aneurysm

•Dissection

CUTANEOUS

VASCULITIS

Cryoglobulinemic

vasculitis

ANCA associated

vascilitidis

Kawasaki disease Polyarteritis nodosa

Urticarial vasculitis

Henoch Schonlein

purpura

• Pulm renal syndrome

• Maculopapular rash

• Periungual & perineal desquamation

• Raynaud’s phenomenon

• Acrocyanosis

• by cold

• Starbust livedo reticularis

• S/C nodules

• Digital gangrene

• Purpura, colic, diarrhoea, nephritis

• Annular urticarial plaques

• HUVS/SLE,NUV

Primary cutaneous small vessel vasculitis

Idiopathic cutaneous vascilitis

Without significant extracutaneous / systemic

involvement

May also include

Normocomplementemic urticarial vasculitis

Essential mixed cryoglobulinemia

Acute hemorrhagic edema of infancy

Mimics of cutaneous vasculitis

Vascular disorders

PLC

Perniosis

Vascular occlusive disease

DIC

Thrombocytopenia

TTP

Homocystinuria

Embolic states

Sneddon’s syndrome

Cholesterol embolism

Purpura

Platelet deficiency

Drug-induced

Dermatoses

Schamberg’s disease

Miscellaneous

Insect-bite reaction

Cutaneous lymphoma

Mimics of systemic vasculitis

Antiphospholipid antibody syndrome

Drug-induced

Cocaine, amphetamines, ergot-derivatives

Infection

SABE

Embolism

Cardiac myxoma

Malignancy

Test for

Initial screening CBC with DLC ESR Urine analysis Stool for occult blood Creatinine Liver function tests CXR Infection screen Hepatitis B and C Cutaneous Bx - H&E & DIF

Proceed further – based on

Available clinical clues / lab findings

Caliber of involved vessels

Severity of disease process

Serologocial ANA ANCA Anti-ds DNA RF

Histopathology/DIF

Kidney

bone marrow

lung

Serum-Cryoglobulins Complement (CH50, C3, C4) Protein electrophoresis Immunofixation

GI evaluation /stool occult blood Nerve conduction study HIV USG Angiography Ophthalmological evaluation

Additional evaluations

Histopathological confirmation required in most cases

cannot stand by itself

considerable overlap in pathological patterns

not diagnostic for specific syndromes

Can be focal / segmental

Not all vessels may be involved

Ideal time -18-36 hrs of age of lesion

Adequate depth including subcutis if MVV

Non-ulcerated site / nodule / white centre of a livido segment / active border of ulcer

Most proximal part of the limb

Histopathology

Histopathological subtypes

Polymorphonuclear-LCV

Lymphocytic- EM, EN (late stages)

Granulomatous-WG, infective, EI, nodular vasculitis

Eosinophilic-CSS, drug eruptions

Hyalanizing vasculitis- atrophie blanche

LCV defined histopathologically by:

Polymorphonuclear neutrophil infiltrate

Affecting superficial post-capillary venules

Fibrinoid deposits in and around vessel wall

Endothelial swelling

Extravasation of RBCs

Karyorrhexis or leukocytoclasia

Fresh non-infarcted most proximal lesion – preferably <6 hrs maximum upto 24 hrs old

Dependent areas – NO

Lesional skin > non-lesional skin

IgA most frequent

Presence of IgA associated with renal involvement but not with its severity

Presence of IgG/IgM /absence of IgA related to presence of cryoglobulins

(Barnadas MA, et al. Int J Dermatol 2004; 43: 19-26)

Direct immunofluorescence

Indications Interpretation

Cryoglobulins Cryoglobulinemic vasculitis Abnormal LFT High RF

high clinical suspicion- 3 –ve results during active flare up False +ve True +ve indicative of Hep C infec 90% T-II & 70% T-III

Complement Urticarial vasculitis S/S of SLE

Cryoglobulinemic vasculitis CTD-SLE/RV/SS Anti C1q precipitins –HUV

ANA S/S of CTD Systemic findings Medium vs wall

UV(low titre 30-50%) CV (20%)

When to order?

• Pulmonary hemorrhage

• Recurrent / long standing - sinusitis / otitis

• Orbital mass

• Glomerulonephritis

• Granulomatous vasculitis

Interpretation

• Indicate pauci-immune vasculitidis DIF -ve

Antineutrophilic cytoplasmic antibody (ANCA)

Seen in <5% of N population

seen in RA, SLE, UC, Crohns, 1° biliary cirrhosis, autoimmune hepatitis, chronic infection

Sensitivity 70%- may postpone need for invasive lung or kidney biopsy

Usually either P-ANCA or C- ANCA

If both suspected drug induced vasculitis

For monitoring disease activity especially in WG

ANCA

Comparison of the ANCA-associated vasculitidis ANCA WG

C-ANCA 75-80% P-ANCA 10-15%

Microscopic polyangiitis

C-ANCA 25-35% P-ANCA 50-60%

Churg-Strauss syndrome

C-ANCA 10-15% P-ANCA 55-60%

Necroptizing granulomas

+ - +

Asthma / eosinophilia

- - +

Pulmonary +++ ++ +++

Renal +++ +++ ++

Cutaneous ++ ++ ++

ENT +++ + ++

Musculoskeletal ++ ++ ++

Neurologic ++ + +++

Gastrointestinal ++ ++ ++

Disease C-ANCA (%) P-ANCA (%)

Wegener’s granulomatosis 75-80 10-15

Microscopic PAN 25-35 50-60

Churg-Strauss syndrome 10-15 55-60

Vasculitis Therapy Literature - Problems

1. Numbers small

2. RCT ???

3. Blinding?

4. How to eliminate spontaneous resolution?

5. Different etiologies, associations & systemic

involvement

6. Where are the follow up studies?

7. Why is there such under-reporting?

Exclusion / treatment of systemic disorders

Remove / treat the cause if any

In the absence of systemic involvement, even cutaneous LCV of

long duration not life threatening

management strategies effective but with limited S/E

Aim of therapy

Comfort the patient / reduce symptoms

Prevent extensive cutaneous infarction & systemic

complications

Management

PCSVV - often single, episodic, self limited disease

1st line treatment Conservative therapy

Conservative therapy

Bed rest, elevation of lower extremities

Warming

Compression hosiery

NSAIDs

Anti-histamines

Avoid tight clothing / trauma

Elimination diet

Antibiotics– suspected infection induced

(none of the conservative measures significantly modify the disease course or prevent recurrences)

Callen JP. South Med J 1987; 80: 848-51.

Five pts with hypersensitivity vasculitis and h/o allergy –elimination diet-complete remission in 4, partial in 1-challenge tests-relapse on re-introducing1

Crossover randomised trial of low antigen diet in 24 pts with mixed cryoglobulinemia 2

So Search for a history of allergy If positive – challenge tests Elimination diets for positive tests not routinely recommended as dual occurrence of food intolerance and allergic vasculitis extremely rare

1. Clin Exp Rheumatol 1992; 10:131-5 2. Am J Med. 1989 Nov;87(5):519-24.

Elimination diet

Alleviate pruritus

Block histamine induced endothelial gap formation with

resultant trapping of immune complex

May be sometimes effective in controlling urticarial lesions

Antihistamines

Act by

COX chemotactic metabolites for eos, neu

Used in

eosinophilic vasculitis, UV, EN (case reports)

constitutional, jt complaints

effect on skin lesion ∓

indomethacin most often used

Benefits

Cheap

Usually no severe S/E

Non-toxic

Problems

Drug induced vasculitis/ other reactions with aspirin, salicylates

Common S/E – GIT and renal

NSAIDs

Nodular, ulcerative or vesiculobullous form

Significantly symptomatic

Recurrent

With systemic involvement

Associated disease

Need for Systemic medications ?

Drug Evidence (in LCV)

Dapsone D

Colcichine C

Pentoxyphylline D

Antimalarials D

Thalidomide D

Steroids C

Immunosuppressives D

I/V Ig D

Plasmapheresis D

Biological therapies D

Treatment modalities

Antiinflammatory with anti-neutrophilic effects :

Dapsone

Used in SS, EED, PG, DG & vasculitis – like HSP

Hypo-complementaemic urticarial vasculitis

Cutaneous PAN

EED

Behcet’s syndrome

LCV

↓ PGD2 alternative complement lysosomal activation active O2 metabolites

IgG and IgA MPO Chemotaxis Neutrophil adherence

Alone or with pentoxyphylline / colcichine

Evidence -anecdotal case reports(level D) or case series in

the case of HSP(level C), but part of many reviews

• Dose: 150-200 mg/day

Side effects –

Anemia (hemolysis)

Methemoglobinemia

Neuropathy

Laboratory testing

G6PD

CBC, LFT

caution in pts with CVS

or pulmonary

complications

Acts by Inhibiting chemotaxis, leukocyte motility, adhesion & lysosomal degranulation

Use in LCV Two open trials –shown good response but relapse on withdrawl response on re-starting1,2

single prospective randomised study no response (LCV was refractory to other therapies, trial not blinded, 3 patients responded but relapsed on withdrawing colcichine)3

1. Arch Dermatol. 1995 Dec;131(12):1399-402 2. JAAD. 1985 Aug;13(2 Pt 1):193-200 3. Arch Dermatol. 1979 Nov;115(11):1303-6.

Colchicine

Used for

HSP for cutaneous lesions– alone / combined with aspirin

Behcet’s syndrome

HUV

NUV,

cryoglobulinemic vasculitis

Dose-0.6-1.8 mg/day

Side effects

GI, burning of throat / skin,alopecia,agranulocytosis, aplasticc anemia, myopathy, peripheral neuritis, leukopenia, teratogenesis, chromosomal non-disjunction, azopsermia

Acts by:

neutrophil adhesion, superoxide

Changes in cell membrane fluidity-Rheological agent

Inhibition of TNF-

Used in

Behcet’s disease

Cutaneous – PAN,

LCV with polyeythema vera

Combined with Dapsone for UV and LCV

livedo vasculitis( atrophie blanche) PLEVA

Kawasai disease ±

Dose 400mg TDS

Only major S/E hypersensitivity

Pentoxyphylline

Efficacy limited to urticarial vasculitis

no report of use in CSVV

Dose- 200-400 mg/day

Antimalarials

Anti-inflammatory, immunomodulating and anti-angiogenic

Effects on CD4 T cells, interleukin, IFN- & VEGF

Used in

Behcets disease

Lucio phenomenon

Cryoglobulinemic vasculitis

Refractory HSP

Recommended only for severe/refractory cases –risk of side

effects

Thalidomide

Often used

• 60mg prednislone used in 12 patients with chronic recurrent small

vessel vasculitis-avg 40 months- complete remission-none,

partial- 4, no benefit in 8-tapering led to reactivation1

• 10-60 mg prednislone used in all 16pts UV and 23 (out of25) pts

with non-urticarial LCV refractory to other therapies2

• Evidence –only reports, no randomised, prospective studies,

mentioned in many reviews

• LCV-C/D

• ANCA associated vasculitidis –A/B

1. JAMA.1982; 247(14):1994-1998. 2. South Med J. 1987;80(7):848-851.

Experience with steroids

Acute/single episode not responding to neutrophilic inhibitors

Severe ulcerative/necrotic/ vesiculobullous cutaneous lesions

GI bleeding

Acute GN

Peripheral neuropathy with impending palsy

HSP nephritis

Cutaneous PAN

ANCA associated vasculitidis

Use with caution/shorter duration-renal & CNS manifestations of HCV associated CV

Relative contra-indication-HBV-PAN, Kawasaki disease

Indications for steroids

Advise

• In LCV- rebound very common - slow tapering

• Monotherapy not recommended for recurrent / chronic PSVV (>4 episode/yr)

Immunosuppresives

As steroid sparing agents

Rapidly progressive disease with systemic involvement

refractory to steroids/adjuvant to steroids

Large vessel involvement

More recurrent chronic symptomatic disease

Azathioprine

Two studies

used in 7 pts – good response in all1

used in 6 pts – alone or combined with steroids /

colcichine – complete control (2), partial response

(3), no response (1)2

Recommended as monotherapy or with low dose

prednisolone

1. Callen JP, et al. South Med J 1987; 80: 848-51.

2. Callen JP, et al. Arch Dermatol 1991; 127: 515-22.

Cyclophosphamide

Single study

Given in 6 pts refractory to steroids, Complete

remission – none, partial improvement – 2,

No benefit – 41

Recommended primarily for systemic vasculitis

1. Cupops TR, et al. JAMA 1982; 247: 1994-8

Drug Opinion Dose

Mycophenolate

mofetil

Helpful in systemic vasculitidis

No reported cases in PCSVV

Upto 2 g total daily

Cyclosporine Good efficacy for acute disease

with short-term use

2.5-5 mg/kg/day

Methotrexate Not indicated, few reports with

LCV

Many cases of inducing LCV

25 mg/wk

Use of potentially life threatening to treat benign course

of chronic cutaneous vascilitis in the absence of

compelling evidence of their efficacy – difficult to justify

Intravenous immunoglobulin

Pooled plasma of donors with

IgG, traces of IgA, cytokines and immunomodulators, normal

antibodies

Acts by neutralisation of Abs/interference with Ab production

Used for severe/ refractory /systemic disease /with

contraindications to other therapies

Used in:

Cutaneous PAN

EMC,HUVS, livedoid vasculitis

Gi and renal manifestations of HSP

FDA approved -Kawasaki disease (2g/kg single dose)

Plasmapheresis

Use in refractory cases of LCV

Recommended for systemic vasculitidis

Especially those with associated infection –where

steroids and immunosuppressives contraindiacated

Biologicals Infliximab

Chimeric monoclonal anti- TNF- antibody

cutaneous PAN

Deep cutaneous vasculitis

Rheumatoid vasculitis

ANCA associated vasculitidis

Infliximab but not eternacept may be for remission in refractory cases

• Caution: reports of TNF- inhibitors induced vasculitis

Adalimuab

• Human monoclonal anti-TNF- antibody

• Used in Takayasu atreritis and rheumatoid vasculitis

Rituximab

• Monoclonal humanized antibody against B cell specific

CD20

• used for HUVS with angioedema

• Cryoglobulinemic vasculitis/nephropathy

Secondary to bacterial/fungal/parasitic infections

Sepsis screen

Antimicrobials

may require CS only in very rare cases (systemic involvement) but no immunosuppressives

HBV-PAN

Incidence now <5% ,

Overt, GI, kidney common, Cutaneous symptoms –rare

t/t – vidarabine, lamivudine, INF-, plasma exchange (as it rapidly clears the immune complex)

Cotrimoxazole in wegeners granulomatosis

Vasculitis secondary to infection

HCV – associated with cryoglobulinemia – type II / type

III

IFN & Ribavarin

Plasma exchange for rapidly progressive peripheral

neuropathy & chronic leg ulcers, not for purpura

Rituximab – improves vascular but may cause a 2-fold

of HCV

HIV associated vasculitidis

Antivirals (HAART), plasma exchange– usually one shot

disease– not recurring and usually 1-3 month of therapy

effective

Systemic vasculitis- European Vasculitis Study (EUVAS)

Stage Definition1

Localised Restricted to upper and/or lower airways without constitutional symptoms or systemic vasculitis

Early systemic disease Localised WG with constitutional S/S Multifocal WG MPAN with threatened organ function

Generalised organ threatening disease

With constitutional symptoms Threatened organ function SCr <5.7 mg/dl

Severe renal vasculitis & imm. life threatening dis.

Rapid progressive renal failure with or without diffuse alveolar hemorrhage

Refractory/relapsing dis. intolerant to standard therapy Progressive despite 6 weeks of appropriate regime

1.Mayo Clin Proc.1997;72(8):737-747.

Stage Treatment (WG / MPAN)

Localised Cotrimoxazole ± Corticosteroids

Early systemic disease Methotrexate + Corticosteroids

Generalised organ

threatening disease

Induc. Cyclophosphamide + CS

Maintenance Azathioprine + CS

Plasma exchange – no additional role

Severe renal vasculitis &

imm. Life threatening dis.

Induc. Cyclophosphamide + CS + PEX

Maintenance Azathioprine + CS

Diffuse pulmonary

hemorrhage

Induc. Cyclophosphamide + pulse

Methylprednisolone + PEX

Maintenance Azathioprine + CS1

1. JAMA.2007;298(6).659-669.

Management guidelines for systemic vasculitis

Disease state Treatment (Churg-Strauss syndrome)

FFS 1 • Induc. Cyclophosphamide + CS •Maintenance – less toxic immunsuppressants

FFS =0 • Induc. CS •Maintenance – low CS if persistent asthma

Disease state Treatment (WG, MPAN & CSS)

Refractory / relapsing dis.

•Anti-thymocytes globulin • IVIg •Newer – etoposide, INF-, leflunamide •Anti TNF-, immunoablation with high dose cytotoxic therapy f/b stem cell rescue

Patient with suspected vasculitis

Rule out mimics of vasculitis

Establish diagnosis

Clinical findings, lab work-up, Bx

Evaluate for underlying

cause

Sepsis

CTD

Malignancy

drug-intake

Categorize into a vasculitic syndrome

No

HSP Urticarial vasculitis

Cryoglobulinemic vasculitis Cutaneous PAN Kawasaki disease

Systemic involvement

Treat

accordingly

Histopathology

Systemic involvement

ANCA +ve ANCA -ve

Takayasu arteritis

Giant cell arteritis

Granulomatous

Asthma / eosinophilia

Wegener’s granulomatosis

PCSSV

Determine extent of disease

Microscopic PAN No

Churg Strauss

syndrome

Yes

LCV UV HSP

First line Conservative NSAIDs Antihistamines

Antihistamins Indomethacin Dapsone ± Pentoxyphylline Antimalarials Steroids

Conservative

Second line

Dapsone Colcichine Steroids

Colcichine Azathioprine

Steroids Steroids + Aza/ Cyclosporine – Renal Steroids (Abd. Pain / arthritis) Dapsone (Rash)

Third line Thalidomide Azathioprine Low dose MTX / Cyclophos IVIg, PEX

Cyclosporine A PEX IVIg Factor XIII

Therapeutic ladder for management of vasculitis

Acute vasculitis / without systemic symptoms or

ulcerating lesions evaluate for 2° vasculitis

reevaluate at 4 wks

At least once a year serological / clinical re-evaluation in pts

with recurrent / chronic disease, especially if

immunosuppressive therapy is used that may mask occult

systemic disease

Prognosis

Poor if:

• Extensive/severe skin involvement

• Persistent/frequently recurrent eruptions

• Need for persistent steroids

• Associated systemic disease

Risk factors

Paresthesias, fever, absence of painful lesions- systemic

involvement

Cryoglobulins, arthralgias, and normal temperature-

chronic cutaneous disease1

1. Arch Dermatol.1998.134.309-315.

To treat patients who are

Sick and tired

of being

“sick and tired”