CUTANEOUS Vasculitis
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Transcript of CUTANEOUS Vasculitis
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”