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
Drugs,
vaccines,
chemicals,
allergies (1015%

Neoplasm
(5%)

Connective
tissue & other
inflammatory
diseases (1520%)

Infection (1520%)
Idiopathic (4555%)

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

Cryoglobulinemic
vasculitis

Henoch Schonlein
purpura
Purpura, colic, diarrhoea,
nephritis

Raynauds phenomenon
Acrocyanosis
by cold

ANCA associated
vascilitidis
Pulm renal syndrome

Kawasaki disease
Maculopapular rash
Periungual & perineal
desquamation

CUTANEOUS
VASCULITIS

Urticarial vasculitis
Annular urticarial plaques
HUVS/SLE,NUV

Polyarteritis nodosa
Starbust livedo reticularis
S/C nodules
Digital gangrene

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
Sneddons syndrome
Cholesterol embolism

Purpura
Platelet deficiency
Drug-induced
Dermatoses
Schambergs 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

Additional evaluations
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

Histopathology
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

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

Direct immunofluorescence
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)

Indications
Cryoglobulinemic
vasculitis
Abnormal LFT
High RF

Interpretation
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%)

Cryoglobulins

Antineutrophilic cytoplasmic antibody (ANCA)

When to order?

Pulmonary hemorrhage

Recurrent / long standing - sinusitis / otitis

Orbital mass

Glomerulonephritis

Granulomatous vasculitis

Interpretation
Indicate pauci-immune vasculitidis DIF -ve

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

Comparison of the ANCA-associated vasculitidis

ANCA

Necroptizing
granulomas
Asthma /
eosinophilia
Pulmonary
Renal
Cutaneous
ENT
Musculoskeletal
Neurologic
Gastrointestinal

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%
+

+++
+++
++
+++
++
++
++

++
+++
++
+
++
+
++

+++
++
++
++
++
+++
++

Disease

C-ANCA (%)

P-ANCA (%)

Wegeners granulomatosis

75-80

10-15

Microscopic PAN

25-35

50-60

Churg-Strauss syndrome

10-15

55-60

Vasculitis Therapy Literature - Problems

1.
2.
3.
4.
5.
6.
7.

Numbers small
RCT ???
Blinding?
How to eliminate spontaneous resolution?
Different etiologies, associations & systemic
involvement
Where are the follow up studies?
Why is there such under-reporting?

Management
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

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.

Elimination diet

So

1.
2.

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

Antihistamines
Alleviate pruritus
Block histamine induced endothelial gap formation with
resultant trapping of immune complex
May be sometimes effective in controlling urticarial lesions

NSAIDs
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

Need for Systemic medications ?

Nodular, ulcerative or vesiculobullous form
Significantly symptomatic
Recurrent
With systemic involvement
Associated disease

Treatment modalities
Drug
Dapsone
Colcichine
Pentoxyphylline
Antimalarials
Thalidomide
Steroids
Immunosuppressives
I/V Ig
Plasmapheresis
Biological therapies

Evidence (in LCV)

D
C
D
D
D
C
D
D
D
D

Dapsone

Antiinflammatory with anti-neutrophilic effects :

PGD2
alternative complement
lysosomal activation
active O2 metabolites

IgG and IgA

MPO
Chemotaxis
Neutrophil adherence

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

Hypo-complementaemic urticarial vasculitis
Cutaneous PAN
EED
Behcets syndrome
LCV

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

Colchicine
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.
2.
3.

Arch Dermatol. 1995 Dec;131(12):1399-402

JAAD. 1985 Aug;13(2 Pt 1):193-200
Arch Dermatol. 1979 Nov;115(11):1303-6.

Used for
HSP for cutaneous lesions alone / combined with aspirin
Behcets 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

Pentoxyphylline
Acts by:
neutrophil adhesion, superoxide
Changes in cell membrane fluidity-Rheological agent
Inhibition of TNF-
Used in
Behcets 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

Antimalarials
Efficacy limited to urticarial vasculitis
no report of use in CSVV
Dose- 200-400 mg/day

Thalidomide
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

Experience with steroids

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.
2.

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

Indications for 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

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
Mycophenolate
mofetil

Opinion
Helpful in systemic vasculitidis

Cyclosporine

Good efficacy for acute disease

with short-term use
Not indicated, few reports with
LCV

Methotrexate

Dose
Upto 2 g total daily

No reported cases in PCSVV

2.5-5 mg/kg/day
25 mg/wk

Many cases of inducing LCV

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

Vasculitis secondary to infection

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

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
Localised
Early systemic disease
Generalised organ
threatening disease

Severe renal vasculitis &

imm. life threatening dis.
Refractory/relapsing dis.

Definition1
Restricted to upper and/or lower airways without constitutional
symptoms or systemic vasculitis
Localised WG with constitutional S/S
Multifocal WG
MPAN with threatened organ function
With constitutional symptoms
Threatened organ function
SCr <5.7 mg/dl
Rapid progressive renal failure with or without diffuse alveolar
hemorrhage
intolerant to standard therapy
Progressive despite 6 weeks of appropriate regime
1.Mayo Clin Proc.1997;72(8):737-747.

Management guidelines for systemic vasculitis

Stage
Localised

Treatment (WG / MPAN)

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.

Disease state
FFS 1
FFS =0

Disease state
Refractory / relapsing
dis.

Treatment (Churg-Strauss syndrome)

Induc. Cyclophosphamide + CS
Maintenance less toxic immunsuppressants
Induc. CS
Maintenance low CS if persistent asthma

Treatment (WG, MPAN & CSS)

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

Clinical findings, lab work-up, Bx
Rule out mimics of vasculitis
Establish diagnosis
Evaluate for underlying
cause
No

Histopathology
Categorize into a vasculitic syndrome

Sepsis
CTD
Malignancy
drug-intake
Treat
accordingly

HSP
Urticarial vasculitis
Cryoglobulinemic vasculitis
Cutaneous PAN
Kawasaki disease
Systemic involvement

Systemic involvement

Microscopic PAN
Churg Strauss
syndrome

No

Yes

PCSSV

ANCA +ve

ANCA -ve

Granulomatous

Takayasu arteritis
Giant cell arteritis

Asthma / eosinophilia

Wegeners granulomatosis

Determine extent of disease

Therapeutic ladder for management of vasculitis

First line

Second
line

LCV
Conservative
NSAIDs
Antihistamines

Dapsone
Colcichine
Steroids

Third line Thalidomide

Azathioprine
Low dose MTX
/ Cyclophos
IVIg, PEX

UV
Antihistamins
Indomethacin
Dapsone
Pentoxyphylline
Antimalarials
Steroids
Colcichine
Azathioprine

Cyclosporine A

HSP
Conservative

Steroids
Steroids + Aza/ Cyclosporine
Renal
Steroids (Abd. Pain / arthritis)
Dapsone (Rash)
PEX
IVIg
Factor XIII

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 temperaturechronic cutaneous disease1

1. Arch Dermatol.1998.134.309-315.

To treat patients who are

Sick and tired
of being
sick and tired