ARTICLE
Auteur(s) : Cord
Sunderkötter1, Anca Sindrilaru2
1Department of Dermatology and Venerology, University
Hospital of Münster, Von-Esmarch-Str. 58, 48129 Münster,
Germany
2Department of Dermatology and Allergology, University
Hospital of Ulm, Maienweg 12, 89081 Ulm, Germany
accepté le 26 Novembre 2005
Conditions and nomenclature for the classification of
vasculitis
Definitions and criteria
Standardized classification of vasculitis is needed to facilitate
not only the diagnosis and management of patients [1] but also for
comparison of results of treatments and for sharpening our
understanding of the pathogenesis and natural history of the
different types of vasculitis. The nomenclature and classification
of the vasculitides have remained an evolving process since the
first classification attempt by Zeek in 1952 [2]. The reasons that
make classification difficult are the only partially evolved
pathogenetic mechanisms, the overlapping clinical features, and the
few pathognomonic signs of the different vasculitic disorders.
Sometimes there does not even appear to be consent on the
definition of vasculitis, which adds to the difficulties in
distinguishing between different forms of vasculitis en route to
agreement on their clinical classification.
What is vasculitis and how does one recognize it?
The definition of vasculitis should be as follows: vasculitis is an
inflammatory condition in which destruction of the wall of blood
vessels by leukocytes is the primary event [3-5]. Although a safe
diagnosis of vasculitis can be made clinically in some cases,
histology offers the most appropriate way to recognize if such a
primary destruction of blood vessels is present. Vasculitides are
histologically characterized by leukocytic infiltration and damage
of the wall of blood vessels, often coupled with compromise of the
lumen. These conditions are easily recognized when vessels are
involved which contain a muscle layer, because leukocytes are not
normally present within these vessel walls. However, when
postcapillary venules are involved, as is the case in
leukocytoclastic vasculitis (LcV), infiltrating cells cannot be
distinguished from transmigrating cells. In this case, indirect
histological criteria must lead to the correct diagnosis, i.e. the
resulting fibrinoid necrosis of the vascular wall with subsequent
extravasation of erythrocytes (hemorrhage), and leukocytoclasia.
Caliber and size of the vessels predominantly involved
determine the clinical picture
The caliber and size of the vessels predominantly involved
influence the clinical features of the different forms of
vasculitis to a large extent, both in the skin and in internal
organs.
For example, panarteritis nodosa [6], as a vasculitic syndrome
involving medium-sized vessels (i.e. medium-sized and small
arteries), presents on the skin with i) subcutaneous nodules
reflecting the inflammation of the medium-sized and small arteries,
ii) livedo racemosa reflecting the impaired blood flow and
subsequent deoxygenation of haemoglobin in some segments of
medium-sized vessels, and iii) necrosis and ulcer due to ischemia
in the tissue area normally supplied by an occluded vessel (( figure 1 )). In the
abdomen inflammation and subsequent weakening of the arterial wall
lead to the characteristic aneurysmal dilatations, e.g. in the
renal artery, while there is no inflammation of small renal vessels
and thus no glomerulonephritis.
In contrast, LcV presents a form of small vessel vasculitis
which primarily affects the postcapillary venules. In the skin this
results in the clinical hallmark of palpable purpura (( figure 2 )), while
involvement of small visceral vessels may result in e.g.
glomerulonephritis.
Because of this relation between vessel size and clinical
symptoms, caliber and size of the vessel predominantly involved
should present the main criteria for the clinical classification of
vasculitis. For further distinction and subdivision, we require
secondary criteria, clinical, serological, histological and
pathophysiological parameters.
Classifications of the American College of Rheumatology (ACR)
and the Chapel Hill Consensus Conference (CHCC)
Two classification systems have gained wide acceptance. In 1990,
the ACR proposed clinical and histologic criteria to distinguish
seven vasculitic entities within the whole field of vasculitides in
order to “provide a standard way to (…) describe groups of patients
in therapeutic, (…) epidemiologic, or other studies” [7]. These
criteria were elaborated by analysing data collected prospectively
from patients with certain diagnoses. This classification system
presented useful information about the clinical and pathological
manifestations of systemic vasculitides and a good approach to
classifying patients into a standardized category for studies.
However, it did not provide a uniform definition of each vasculitis
to the clinician who categorized the patients. As a lack of
standardized diagnostic definitions impairs a systematic
nomenclature and classification, the CHCC came together 4 years
later on the nomenclature of systemic vasculitides and published a
working classification that intended to “reach consensus on the
names for some of the most common forms of non-infectious systemic
vasculitis and to construct (…) definitions” [8]. Thus, the goal
was to construct “a standardized nomenclature system”, rather than
to determine “the clinical or diagnostic criteria required to
classifiy or diagnose individual patients” [8]. It has emphasized
that the size of the vessels involved is the main criterion, but
has also included histopathologic features (e.g. granulomatous
infiltrates in giant cell arteritis), immunohistological findings
(e.g. IgA-containing deposits at the vessel wall in
Henoch-Schönlein- purpura (HSP)), markers of immunodiagnostic
significance (e.g. anti-neutrophil cytoplasmic antibodies (ANCA)),
clinical features including the extent of the process with regard
to the organs chiefly (e.g. the lung in Churg-Strauss syndrome) or
exclusively affected (e.g. the skin in cutaneous vasculitis) [8].
Due to the clear terms and definitions, the CHCC proposal has
become a frequently used nomenclature and classification system.
Neither the ACR nor the CHCC classifications sufficiently
distinguish the different forms of immune-complex vasculitis
Neither the CHCC nor the ACR criteria have been developed for
diagnostic purposes. Therefore they fail in providing an
unambiguous diagnosis in certain cases. Besides, they have focused
on systemic vasculitides as encountered in internal medicine and
therefore have not dealt in detail with those forms which are more
common in dermatology. They thus remained incomplete for e.g.
immune complex-associated vasculitides. This may be one reason why
the criteria for HSP in the ACR system are not distinct enough to
differentiate HSP from other forms of LcV. They do not
differentiate whether immune complexes containing IgA or IgG/IgM
are involved. In addition the ACR defines HSP as a LcV of childhood
(≤ 20 years of age), and so its nomenclature does not include
patients with IgA-mediated LcV of adult age. Such distinctions,
however, are clinically relevant, because i) IgA-associated LcV or
HSP of adult age has a higher rate of severe complications than HSP
in children, and ii) HSP in both ages has a higher rate of systemic
involvement than LcV associated with IgG or IgM containing immune
complexes [5]. Similarly, the CHCC proposal only encompasses a
purely cutaneous leukocytoclastic angiitis. It does not consider
that there is a LcV with IgG or IgM containing immune complexes
which presents with systemic signs such as arthralgias,
glomerulonephritis or abdominal complaints [5, 8]. Thus, neither
classification has an assignment for this form of non
IgA-associated LcV with systemic involvement.
Inclusion of pathophysiological and clinical aspects allows a
prognostically relevant classification of immune complex
vasculitis
To overcome these problems, the definition of certain vasculitides
needs to be supplemented with additional pathophysiological and
clinical criteria as well as surrogate laboratory markers [9].
In table 1( Table 1 ), we present a
modification which has proven to be applicable and practical in our
clinical setting. It pays special attention to the forms
encountered frequently by dermatologists and includes
pathophysiological mechanisms as one important cirterion. It may
serve as a provisional guide for the needs of dermatology and
general medicine until a consensus is reached.
With regard to vasculitis of medium-sized vessels, we advocate
for formal reasons including in this group i) cutaneous PAN as a
subgroup of PAN, and ii) those forms of lobular or septal
panniculitis which are associated with vasculitis. In nodose
vasculitis or erythema induartum Bazin, for example, vessel
inflammation is clearly present and it usually involves vessels in
the pannus, i.e. primarily medium-sized vessels. On strict
histological terms, PAN also represents a form of panniculitis with
vasculitis, as does thrombophlebitis.
With regard to small vessel vasculitis we made detailed
amendments to the group of LcV. They encompass the above mentioned,
clinically relevant distinctions between i) HSP of children and
adult age, or ii) IgG/IgM- and IgA-associated LcV (i.e. HSP)
[5].
Table 1 Clinical classification of vasculitis
(modification of the classification of the American College of
Rheumatology (ACR) [7, 39, 53] and of the Chapel Hill Consensus
Conference (CHCC) [8]
|
Vessels predominantly or exclusively involved
|
Vasculitis
|
|
Aorta and branching vessels
|
- - Takayasu’s arteritis
- - Giant cell arteritis (e.g. temporal arteritis)
- - (Mesaortitis luetica, direct infection of vasa vasorum)
|
|
Medium-sized blood vessels (medium-sized and small arteries and
veins)
|
- 1 Polyarteritis nodosa (6) group
- - Classic (systemic) PAN
- - Cutaneous PAN (without visceral involvement)
- - Kawasaki syndrome / infantile PAN
- 2 Nodose vasculitis in panniculitis
- - Erythema induratum Bazin
- - Erythema nodosum leprosum
|
|
Small-sized blood vessels (postcapillary venules, arterioles,
rarely capillaries) [3,5,20)]
|
- 1 Systemic ANCA-associated vasculitis (also involving
medium-sized vessels such as small arteries, but mostly small
vessels. LcV of postcapillary venules is most frequent form of
cutaneous involvement in Wegener granulomatosis [54])
- - Wegener granulomatosis
- - Microscopic polyangiitis
- - Churg-Strauss syndrome
- 2 Immune complex-associated vasculitis (most common form of
LcV)
- 2.1 Immune complex-mediated damage of vessel wall as main
pathogenic factor for LcV
- - LcV with predominantly perivascular deposition of
IgA-containing immune complexes (Henoch-Schönlein Purpura)
(HSP)
- - HSP of children (≤ 20 years of age)
- - Hemorrhagic edema of childhood (≤ 2 years)
- - HSP of adult age (> 20 years of age)
- - LcV with predominant perivascular deposition of
IgG/IgM-containing immune complexes (hypersensitivity vasculitis,
necrotizing or allergic vasculitis)
- - Cutaneous LcV (without apparent systemic involvement)
- - IgG/IgM-associated LcV with systemic involvement
- - Serum-sickness
- 2.2 Immune complex-mediated damage of vessel wall as major, but
not the only pathogenic factor
- - Cryoglobulinemic vasculitis (intravascular gelation in
addition to immune complex-mediated damage of vessel wall)
- - Urticarial vasculitis (factors causing urticae and/or
disturbances in complement in addition to immune complex-mediated
damage of vessel wall)
- - normocomplementemic urticarial vasculitis (NUV)
- - hypocomplementemic urticarial vasculitis (HUV) /
- - syndrome of hypocomplementemic urticarial vasculitis
- - (HUVS)
- 3 Complex forms of LcV (immune complexes may be present, but
other major pathogenic factors come into effect)
- - LcV in conjunction with connective tissue disease (Sjögrens’
syndrome, SLE, RA)
- - Acral LcV and vasculopathy in SLE
- - LcV in conjunction with neutrophil dermatosis (M.
Behcet)
- - Erythema elevatum et diutinum
- - Granuloma faciale
- 4 Vasculitis combined with coagulopathy
- - bacteremia, sepsis, pupura fulminans
(Shwartzman-reaction)
- 5 Vasculitis due to direct infection of endothelial
cells
- - e.g .infection with certain rickettsia
|
The terms “vasculitis of the skin” or “cutaneous
vasculitis”
Generally, nearly all types of vasculitis may affect vessels of the
skin, be it those of the superficial vascular plexus such as in
LcV, or those of the deeper vascular plexus, such as in PAN. The
term cutaneous vasculitis may refer to an inflammation of vessels
restricted exclusively to the dermal vessels, but may also refer to
an inflammation of vessels in the skin as part of a systemic
vasculitis. This especially applies for LcV, as the CHCC defines
cutaneous leukocytoclastic angiitis or LcV as a form restricted
only and exclusively to the skin, while on the other hand LcV may
present as a sign in several forms of systemic vasculitis such as
systemic ANCA-associated vasculitis. One should also consider that
the absence of apparent signs for systemic involvement does not
rule out inflammation of visceral vessels, as the latter could
remain undetected due to an only transient occurrence or to low
sensitivity of our diagnostic means (e.g. hemoccult).
Our suggestion for clinical practice would be to use the
provisional term “vasculitis of the skin”, or, if present, “LcV of
the skin” for a first “working” diagnosis, and then strive for a
more precise and correct diagnosis by virtue of the various
diagnostic procedures.
The terms “primary” and “secondary” vasculitis
These terms also have caused some confusion, which could be solved
partially by reference to the previous paragraph.
Primary vasculitis of the skin would be a form of vasculitis
manifesting exclusively on the skin. It would thus be identical to
cutaneous leukocytoclastic angiitis as defined by the CHCC
(similarly, there may be primary vasculitis of the central nervous
system [10]).
Secondary vasculitis of the skin would then refer to vessel
inflammation of the skin in conjunction with:
- i) a systemic form of vasculitis; i.e. LcV on the skin
in patients with Wegener’s granulomatosis, MPA and Churg-Strauss
syndrome, or vasculitis of deeper vessels (and septal panniculitis)
in classical systemic PAN;
- ii) a multisytem disease, i.e. LcV in connective tissue
disease (SLE), or LcV associated with malignancies, i.e. LcV in
leukaemia.
In a more general sense primary vasculitis would be a vasculitis
at any organ in which inflammatory damage of blood vessels is the
main and driving force of the disease, i.e. vasculitic cutaneous,
renal, or cerebral manifestations of most of the vasculitides
listed in table 1, such as classical PAN, Wegener’s granulomatosis,
MPA and Churg-Strauss syndrome. In this context secondary
vasculitis would be a vasculitis which could occur at any organ as
an additional symptom in a multisytem disease, i.e. cutaneous,
renal, or cerebral vasculitis [10] in association with SLE,
malignant tumor, or infections.
One minor reservation should be made: when considering the
various non-vascular symptoms in Wegener’s granulomatosis and
Churg-Strauss syndrome, one should remain open to the possibility
that there are other driving forces in these diseases than mainly
vasculitis.
As it is not always clear in which context the terms “primary”
and “secondary” vasculitis are used, one should briefly point this
out when applying them.
Diseases or conditions not presenting forms of true
vasculitis
Pyoderma gangrenosum, Sweet’s syndrome
There are other skin diseases which present with inflammatory
changes around the vasculature and with leukocytoclasia, such as
pyoderma gangrenosum and Sweet’s syndrome. They have been subsumed
by some authors under the term (cutaneous) vasculitis [11].
However, as they do not primarily affect blood vessels as a primary
target, these conditions are not vasculitis in sensu strictu and
should better be classified as neutrophilic vascular reactions [12]
or neutrophilic dermatoses [13].
Vessel damage in the course of tissue necrosis
Vessel damage or vasculitic alterations also represent a secondary
rather than primary event in conditions where blood vessels are
destroyed by physical trauma or its sequela (e.g. after laser
therapy), or where vessel damage occurs secondary to destructive
inflammatory processes of the surrounding tissue, such as in
abscess formation.
Pigmented purpura (purpura pigmentosa or capillaritis)
Pigmented purpura (purpura pigmentosa or capillaritis) presents
with erythrocyte extravasates, but although a dense lymphocytic
infiltrate is usually present, fibrinoid necrosis or destruction of
the small blood vessels could not be demonstrated. Yet,
lymphocyte-mediated damage of the vessel wall is possible in
certain conditions [14]. It could represent a distinct group of
vasculitides, but has not been classified yet [14].
Livedo vasculopathy
Livedo vasculopathy is a syndrome characterized by livedo
reticularis and recurrent painful ulceration with predilection for
the malleolar site, leaving residual white atrophic scars (atrophie
blanche). It is an occlusive vasculopathy due to a hypercoagulable
state, although the biochemical nature of the hypercoagulable state
may not always be defined or detectable yet. The term livedo
vasculitis is a misnomer for this disease, as vascular
inflammations are a secondary event. Livedo vasculopathy, however,
shares one prominent clinical sign, i.e. livedo racemosa, with the
vasculitis of medium-sized vessels (e.g. PAN). Livedo racemosa is a
distinct type of livedo reticularis with a characteristic irregular
bluish pattern in the skin resembling a broken fishing net. The
bluish colour reflects blood with a higher percentage of
deoxygenated haemoglobin at sites of impaired blood flow. The
obstruction results from partial or complete occlusion at single
sites of the cutaneous vasculature, due either to coagulopathy as
in livedo vasculopathy or to vasculitis as in PAN (( figure 1 )) [6, 15].
Modified clinical classification of vasculitis with a focus on
leukocytoclastic vasculitis (based on the classification of the ACR
[7] and of the CHCC [8])
Most forms of vasculitis in the skin are mediated by
immunopathogenic mechanisms. These encompass: the formation of
immune complexes, the production of anti-neutrophil cytoplasmic
antibodies, or pathogenic T cell responses and granuloma formation.
There are a few vasculitic syndromes that are caused by direct
microbial invasion of endothelial cells (e.g. mesaortitis luetica
or some forms of tick-bite fever caused by Rickettsia).
Vasculitis involving predominantly large blood vessels (aorta
and branching vessels)
Clinical and pathophysiological aspects relevant for
classification
One of the histologic hallmarks of certain vasculitic syndromes
with involvement of medium sized and large vessels is the presence
of granulomatous inflammation. In giant cell arteritis and
Takayasu’s arteritis, the granulomas are restricted to the vessel
wall leading to destruction of the internal elastic lamina. The
detection of clonally expanded CD4+ T cells of TH-1 type
in the lesional tissue indicates that the granulomatous
inflammation could be due to an aberrant TH-1 cell response to
autoantigens and/or environmental insults, such as infections [16].
Giant cell arteritis
It rarely causes symptoms on the skin. They may present as nodules
over the scalp, but also lead to necrosis when branches supplying
the skin are heavily involved (( figure 3 ), tables 2A,B(
Table 2A )( Table
2B )).
Table 2A Giant cell arteritis - ACR criteria [55]
|
1. Age at disease onset ≥ 50 years (development of symptoms or
findings starting at age 50 or older)
|
|
2. New headache (new onset or a new type of localized pain in the
head)
|
|
3. Claudication of jaw, tongue, or on deglutition (development or
worsening of fatigue or discomfort in muscles of mastication,
tongue or swallowing muscles while eating)
|
|
4. Temporal artery abnormality (temporal artera tenderness to
palpation or decreased pulsation unrelated to arteriosclerosis of
cervical arteries)
|
|
5. Scalp tenderness or nodules (development of tender areas or
nodules over the scalp, away from the temporal artery or other
cranial arteries)
|
|
6. Abnormal artery biopsy (biopsy specimen with artery showing
vasculitis characterized by a predominance of mononuclear cell
infiltration or granulomatous inflammation, usually with
multinucleated giant cells)
|
Table 2B Giant cell (temporal) arteritis – CHCC
definition [8]
|
• Granulomatous arteritis of the aorta and its major branches, with
a predilection for the extracranial branches of the carotid
artery.
|
|
• Often involves the temporal artery
|
|
• Usually occurs in patients older than 50 and often is associated
with polymyalgia rheumatica.
|
Takayasu arteritis
The major symptoms are claudication and blood pressure differences
(tables 3A,B( Table 3A )( Table 3B )). There are reports of at least 10
cases which also present small vessel vasculitis on the skin [17],
leading to the assumption that Takayasu’s arteritis may encompass a
small vessel vasculitis, including the vasa vasorum.
Table 3A Takayasu arteritis, ACR criteria [56]
|
1. Age at disease onset ≤ 40 years (development of symptoms or
findings related to Takayasu arteritis at age ≤ 40 years)
|
|
2. Claudication of extremities (development and worsening of
fatigue and discomfort in muscles of 1 or more extremity while in
use, especially the upper extremities)
|
|
3. Decreased brachial artery pulse (decreased pulsation of 1 or
both brachial arteries)
|
|
4. Blood pressure difference > 10 mm Hg (difference of >
10 mm Hg in systolic blood pressure between arms)
|
|
5. Bruit over subclavian arteries or aorta (bruit audible on
auscultation over 1 or both subclavian arteries or abdominal
aorta)
|
|
6. Arteriogram abnormality (arteriographic narrowing or occlusion
of the entire aorta, its primary branches, or large arteries in the
proximal upper or lower extremities, not due to arteriosclerosis,
fibromuscular displasia, or similar causes; changes usually focal
or segmental)
|
Table 3B Takayasu arteritis, CHCC definition [8]
|
• Granulomatous inflammation of the aorta and its major
branches.
|
|
• Usually occurs in patients younger than 50.
|
Vasculitis involving predominantly medium-sized blood vessels
(medium-sized and small arteries and veins)
Panarteritis nodosa (systemic and cutaneous PAN) Clinical and
pathophysiological aspects relevant for classification
PAN involves medium-sized and small arteries and presents on the
skin with subcutaneous nodules, livedo racemosa and ischemic
necrosis. In the abdomen characteristic aneurysms are seen by
angiography, e.g. in the renal artery, while there is no
glomerulonephritis (tables 4A,B,C( Table
4A )( Table 4B )( Table 4C )).
Cutaneous PAN should be differentiated from classical or
systemic PAN. The cutaneous symptoms are similar (( figure 1 )) and they may
also be accompanied by elevated sedimentation rate, slight fever,
arthralagia or myalgia, sometimes even neuropathies. But it does
not present with arterial hypertension, leukocytosis, or disease of
the visceral arteries. As this form is mostly seen by
dermatologists it is not generally accepted yet as a sub-entity by
rheumatologists. It is, however, doubtful, if cutaneous PAN ever
proceeds to classical PAN. Nevertheless the latter has to be
excluded, which may require repetition of some diagnostic
procedures. The first line treatment should be much less aggressive
than in systemic PAN. Often colchicine or dapsone are
sufficient.
Table 4A Panarteritis nodosa, ACR criteria [57]
|
1. Weight loss ≥ 4 kg (loss of 4 kg or more of body weight since
illness began, not due to dieting or other factors)
|
|
2. Livedo reticularis (Mottled reticular pattern over the skin of
portions of the extremities or torso)
|
|
3. Testicular pain or tenderness (pain or tenderness of the
tesicles, not due to infection, trauma or other causes)
|
|
4. Myalgias, weakness or leg tenderness (diffuse myalgias
(excluding shoulder and hip girdle) or weakness of muscles or
tenderness of leg muscles)
|
|
5. Mononeuropathy or polyneuropathy (development of mononeuropathy,
multiple mononeuropathies, or polyneuropathy)
|
|
6. Diastolic blood pressure ≥ 90 mm Hg (development of
arterial hypertension with the diastolic BP higher than 90
mmHg)
|
|
7. Elevated BUN or creatinine (elevation of blood urea nitrogen ≥
40 mg/dl or creatinine > 1.5 mg/dl, not due to dehydration or
obstruction)
|
|
8. Hepatitis B virus (presence of hepatitis B surface antigen or
antibody in serum)
|
|
9. Arteriographic abnormality (arteriogram showing aneurysms or
occlusion of the visceral arteries, not due to arteriosclerosis,
fibromuscular displasia, or other noninflammatory causes)
|
|
10. Biopsy of small or medium-sized artery containing PAN
(histologic changes showing the presence of granulocytes or
granulocytes and mononuclear leukocytes in the artery wall)
|
Table 4B Panarteritis nodosa (classic polyarteritis
nodosa) CHCC definition [8]
|
• Necrotizing inflammation of medium-sized or small arteries
without glomerulonephritis or vasculitis in arterioles,
capillaries, or venules
|
Table 4C Kawasaki disease, CHCC definition [8]
|
• Arteritis involving large, medium sized, small arteries, and
associated with mucocutaneous lymph node syndrome
|
|
• Coronary arteries are often involved
|
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• Aorta and veins may be involved
|
|
• Usually occurs in children
|
Panniculitis with vasculitis
Histologically, PAN represents a mainly septal panniculitis with
vasculitis [18, 19]. There are two relevant forms of mainly lobular
panniculitis with vasculitis: erythema nodosum leprosum and nodose
(or nodular) vasculitis of various etiologies (among which the term
erythema induratum Bazin might be reserved for the tuberculous
reaction).
Vasculitis of small sized vessels
The basic and common pathophysiological denominator in all these
different forms of LcV appears to be a constellation in which
granulocytes are activated for release of toxic products close to
endothelial cell due to alterations of the vessel wall which
interfere with normal diapedesis [4, 20].
Most forms of small vessel vasculitis are associated either with
ANCA or with immune complexes. The former can well be determined by
serological tests and are therefore apt as criteria for
classification. Methods for determining immune complexes in serum
are much less sensitive. However, in LcV the histology is
sufficiently characteristic for diagnosis and classification.
Systemic, ANCA-antineutrophil cytoplasmic antibodies-associated
vasculitides (formerly pauci-immune vasculitis)
Systemically these vasculitides often cause severe symptoms,
depending on a varying pattern of involvement. Among them are
glomerulonephritis, pulmonary hemorrhage, disturbances of CNS
functions and the serious clinical sequela such as renal or
pulmonary insufficiency, arterial hypertension or neuritis. In
contrast to the CHCC, the ACR had not yet included microscopic
polyangiitis (MPA) as an individual entity in its classification
(tables 5-7( Table 5A )( Table 5B )( Table 6A
)( Table 6B )( Table
7 )).
Clinical and pathophysiological aspects relevant for
classification
ANCA are a heterogenous group of autoantibodies. Most of them
show specificity for either proteinase 3 (cANCA) or myeloperoxidase
(pANCA). They are regularly (but not exclusively) found in
Wegener’s granulomatosis, MPA and Churg-Strauss syndrome. One
reported effector function of these autoantibodies is stimulation
of neutrophils to produce reactive oxygen species and to release
proteolytic enzymes, similar to their response to immune complexes
[21, 22]. There is a causal link between passively transfered ANCA
and the development of glomerulonephritis and vasculitis,
demonstrated in mouse models [21-23]. Wegener’s granulomatosis and
Churg-Strauss syndrome, but not MPA, are additionally characterized
by necrotizing granulomatous inflammation of the extravascular
interstitial tissue. As in giant cell arteritis, the clonal and
polyclonal CD4+ T cells derived from lesional tissue and
peripheral blood of Wegener’s granulomatosis exhibit a predominant
TH-1 profile, while a TH-2 cytokine patterns had been reported for
MPA, the form not associated with granulomas [24-26]. The aberrant
granuloma formation is supposed to be secondary to the inflammatory
reaction and tissue necrosis, caused by ANCA-induced activation of
extravascular neutrophils and monocytes [27, 28].
Although ANCA are usually present and detectable in serum of
patients with Wegener’s granulomatosis, MPA and Churg-Strauss
syndrome, cutaneous and renal biopsies of these diseases and of a
form of necrotizing and crescentic glomerulonephritis did not
regularly or only weakly detect deposited immunoglobulines. This
has lead to the term pauci-immune (necrotizing small vessel)
vasculitis and pauci-immune necrotizing and crescentic
glomerulonephritis [29]. However, the failure to detect
immunoglobulines in biopsies does not exclude a pathophysiological
function for either ANCA or for immune complexes in ANCA-associated
vasculitides [30].
Table 5A Wegener’s Granulomatosis, ACR criteria [58]
|
1. Nasal or oral inflammation (development of painful or painless
oral ulcers or purulent or bloody nasal discharge)
|
|
2. Abnormal chest radiograph (chest radiograph showing the presence
of nodules, fixed infiltrates, or cavities)
|
|
3. Urinary sediment (microhematuria (> 5 red blood cells per
high power field) or red cell casts in urine sediment)
|
|
4. Granulomatous inflammation on biopsy (histologic changes showing
granulomatous inflammation within the wall of an artery or in the
perivascular or extravascular area (artery or arteriole))
|
Table 5B Wegener’s Granulomatosis, CHCC definition
[8]
|
• Granulomatous inflammation involving the respiratory tract, and
necrotizing vasculitis affecting small to medium-sized vessels
(e.g. capillaries, venules, arterioles, and arteries).
|
|
• Necrotizing glomerulonephritis is common.
|
Table 6A Churg Strauss Syndrome, ACR criteria [59]
|
1. Asthma
|
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2. Eosinophilia > 10%
|
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3. Neuropathy, mono or poly
|
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4. Pulmonary infiltrates, non-fixed
|
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5. Paranasal sinus abnormality
|
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6. Extravascular eosinophils
|
Table 6B Churg Strauss syndrome, CHCC definition [8]
|
• Eosinophil-rich and granulornatous inflammation involving the
respiratory tract.
|
|
• Necrotizing vasculitis affecting small to medium-sized
vessels.
|
|
• Associated with asthma and eosinophilia.
|
Table 7 Microscopic polyangiitis (microscopic
polyarteritis), CHCC definition [8]
|
• Microscopic polyangiitis + Necrotizing vasculitis, with few or no
immune deposits, affecting small vessels (i.e. capillaries,
venules, or arterioles).
|
|
• Necrotizing arteritis involving small and medium sized arteries
may be present.
|
|
• Necrotizing glomerulonephiltis is very common.
|
|
• Pulmonary capillaritis often occurs.
|
Leukocytoclastic vasculitis (LcV)
LcV is the most frequent form of vasculitis and by far the most
frequent form of vasculitis in the skin. It involves the small
vessels, in particular the postcapillary venules, and it is
associated with apoptosis of infiltrating granulocytes featuring
fragmentation of the nuclei (karyorrhexis or leukocytoclasia). This
feature has lead to the term leukocytoclastic vasculitis and is a
major criterion for classification.
Clinical and pathophysiological aspects relevant for
classification
The clinical hallmark is palpable purpura due to the infiltrate
and hemorrhage (( figure
2 )). LcV can be one symptom of ANCA-associated vasculitis
(“secondary LcV”). However, in most cases LcV is caused by large
immune complexes deposited at the vessel wall. In other forms of
LcV further pathophysiological factors play a role in addition to
immune complexes.
It is important for classification and for the clinical approach
to distinguish between LcV in which the deposited immune complexes
contain primarily IgA (i.e. HSP) from those which contain IgG or
IgM, but not IgA [5, 31], because HSP has a higher frequency and
severity of complications [32].
LcV caused by IgA-containing immune complexes (HSP)
We think that the term HSP should not be used only or generally
for LcV in children (which might happen when using the criteria of
the ACR (table 8a( Table 8A )), but
that it should be reserved for IgA-associated LcV in both children
and adults. As it is usually associated with systemic symptoms, the
criterion “IgA deposits at the vessel wall on immunofluorescence”
could probably be added to the ACR criteria without reducing their
sensitivity [33, 34]. IgA-associated LcV occurs much more often in
children than in adults (80% vs 10-20%) so that HSP could still be
considered a mainly pediatric disease. However, it is important to
recognize that it does occur in adults (figures 2 and 4), and that
in adult age complications are more severe, albeit not more
frequent than in children [34]. Complications are also more
frequent than in IgG- or IgM-associated LcV. Such complications are
e.g. nephritis with subsequent chronic renal failure or
gastrointestinal hemorrhage. The immunofluorescence pattern of
HSP-associated nephritis is indistinguishable from IgA-nephropathy,
i.e. mesangial IgA deposits accompanied by IgG, C3 and properdin
[35]. In children with HSP and nephritis the risk of end stage
renal disease was approximately 3% in unselected studies [36] and
14% in a cohort which had already required a renal biopsy [37].
When in adults there is involvement of kidneys at the beginning of
HSP, chances for complete remission are only about 20% [34]. Also
skin necrosis is frequent in adults with HSP (60%), but rare in
children (< 5%) [33, 34].
Acute hemorrhagic edema of children
It is likely to be a special form of HSP in infants (4 to 24
months of age) with a benign self-limited course.
LcV caused by IgG- or IgM-containing immune complexes
When in LCV there are no IgA-positive vascular depositions as in
HSP, and when there are no signs for either systemic
ANCA-associated or cryoglobulinemic LcV or bacteremic vasculitis,
then it is most likely LcV caused by IgG- or IgM-containing immune
complexes [5]. It is frequent in adults (ca 80%), but rare in
children. It has a more favourable prognosis than IgA-associated
LcV, thus justifying this distinction [32, 33, 38]. The clinical
signs of this form often appear to be limited to the skin. The CHCC
system has classified it as cutaneous leukocytoclastic angiitis
(table 9B( Table 9B )) [8]. Yet,
systemic involvement is possible and encompasses arthralgias,
glomerulonephritis or abdominal complaints [5]. As mentioned above,
there is no assignment for this form of LcV in the classification
of either the CHCC or the ACR. We suggest the term “LcV with
perivascular deposition of IgG/IgM with systemic involvement”
(tables 8A,B, 9A,B( Table 8B )( Table 9A )) [5, 38]. For practical reasons
one could also initiate the term “non IgA-associated LcV with
systemic involvement”, because IgG or IgM are often no longer
detectable at the time of biopsy due to their rapid removal,
whereas IgA persists longer. Thus, when immunofluorescence is
negative despite an unambiguous clinical or histological diagnosis
of LcV, IgG- or IgM-associated LcV is likely, while HSP is
unlikely.
The ACR has established “medication at disease onset” as one
criterion for the classification of hypersensitivity vasculitis
(table 9A) [39]. Indeed, approximately 10-15% of IgG/IgM-associated
LcV occur after intake of medical drugs (NSAID, sulfonamides,
penicilline, cefaclor, diuretics related to hydrochlorothiazide and
furosemide, allopurinol, quinolones, hydralazine, methotrexate,
etanercept, infliximab, but also contraceptives) [5, 40-43].
However, because infections come next in frequency as eliciting
agents (upper respiratory tract, infections with hepatitis B or C,
infections by enterovirus) [40, 41, 43, 44], and because there are
also associations with myeloproliferative or lymphoproliferative
diseases [5], “medication at disease onset” is not a good
distinguishing criterion. As mentioned above, the ACR
classification does not allow to exactly classify a patient who
presents at age 18 with palpable purpura and LcV on histology, as
he could have either HSP or hypersensitivity vasculitis or even
none of the ACR- or CHCC-classified forms, i.e. IgG/IgM-associated
LcV with systemic involvement.
Serum thickness
Serum thickness is charcterized by fever, arthalgia, exanthema
and enlargement of lymph nodes beginning 7 to 14 days after the
first, and 2 to 4 days after renewed exposure to serum from
animals, and it may also occur after intake of penicilline,
sulfonamides or streptokinase [5]. It is not always associated with
typical LcV [5], but may also present as urticarial vasculitis.
There are forms of LcV in which other pathophysiological factors
play a role in addition to immune complexes. They show special
clinical charcteristics which warrant their classification as a
distinct form of LcV.
Cryoglobulinemic LcV
In cryoglobulinemic LcV the immune complexes are cryoglobulines
type II or III, i.e. complexes consisting of human IgG or IgM and
IgM-antibodies directed against them. In addition to causing LcV
these complexes also gelatinize in cold temperatures and thus lead
to occlusion of vessels in exposed areas of the skin (fingers,
toes, nose, ears). This results in more frequent occurrence of
necrosis and ulceration than in other forms of
immune-complex-mediated LcV. Accompanying signs are livedo
racemosa, cold-induced urticaria, panniculitis or acrocyanosis.
Cryoglobulinemia type II is often associated with hepatitis C virus
(HCV) (80-90%). HCV particles and non-enveloped nucleocapsid
protein participate in the formation of these immune complexes and
confer the special physical and chemical properties. Clonal
expansion of corresponding B-cells correlates with a high
intrahepatic viral load. Thus therapies focus on abatement of the
viral load and deletion of B-cell clonalities [45]. In addition a
deficiency of regulatory T cells has been detected in these
patients [46]. Further conditions associated with cryoglobulinemic
LcV are other infections, such as HIV, or autoimmune diseases
(rheumatoid arthritis, SLE, Sjögren’s syndrome), as well as
lymphoproliferative diseases [42, 47].
Urticarial vasculitis
Urticarial vasculitis is associated with marked and persistent
edema, the cause of which is not exactly known. While most cases
are associated with normal complement levels, there is also a
hypocomplementemic urticarial vasculitis (HUV), which is usually
complicated by systemic symptoms [48-50] and should therefore be
considered separately. Among patients with HUV, 22-54% fulfilled
either at presentation or later the ACR criteria for systemic lupus
erythematodes (SLE) and presented a positive lupus band test
besides vascular deposits of immunglobulines [48-50]. Other
associated autoimmune diseases are Sjögren’s syndrome,
cryoglobulinemia or infection with hepatitis C.
The syndrome of hypocomplementemic urticarial vasculitis (HUVS)
is defined according to Wisnieski et al. [48] by persistent HUV,
antibodies against C1q, angioedema (50%), uveitis (30%) and a
severe chronic obstructive pulmonary disease (50%) [48].
Complex forms involving additional factors such as in connective
tissue disease (LE, RA) or in neutrophil dermatoses (M. Behcet)
In these forms immune complexes may be present, but in contrast
to cryoglobulinaemic or urticarial vasculitis they may not be
mandatory, while other major pathogenic factors come into effect,
which are probably equally or even more relevant for the clinical
picture. The nature of these various mechanisms is often unknown.
They may include sustained activation of endothelial cells
resulting in disturbed transmigration and stimulation of
granulocytes in SLE [51], similar to the pathophysiological
condition in bacteremic or septic vasculitis [4]. This may explain
the occurrence of similar clinical symptoms in both conditions. As
such, Osler nodules or Janeway spots appear in bacteremia (e.g.
during infective endocarditis) as well as in acral LcV and
vasculopathy during SLE or SCLE [3-5]. LcV in conjunction with
neutrophil dermatosis (M. Behcet) might result from undue
activation of granulocytes.
We concede that there will be overlaps within this group as well
as between this group and e.g. urticarial or cryogloblunemic LcV.
This may be true as long as we do not have more detailed knowledge
about the underlying pathophysiolgical mechanisms. Yet, it is
clinically justified to distinguish between e.g. cryoglobulinemic
LcV and acral LcV and vasculopathy in SLE or SCLE.
Vasculitis and coagulopathy in bacteremia or sepsis
Hemorrhagic macules, papules or even ecchymoses in bacteremia or
sepsis show signs of LcV on histology, but they are not caused by
immune complexes. According to animal models this form of LcV is
likely to be associated with unphysiological stimulation of both
granulocytes and endothelial cells and the coagulation system by
bacterial products or inflammatory mediators [4, 20]. The increased
coagulability may progress to disseminated intravascular
coagulation (DIC). In purpura fulminans tissue necrosis is caused
additionally by toxins of the causative bacteria (similar to
involvement of toxins in the severe tissue necrosis of necrotizing
fasciitis).
Vasculitis due to direct infection of endothelial cells
There is no consensus yet if infection of endothelial cells and
vessels (e.g. in rickettsiosis) should be subsumed under the term
vasculitis, because one could argue that the primary event is
infection, while inflammation of the wall of the affected vessel is
a secondary event.
However, the inflammatory and histopathological reactions are
similar to those caused by non-infectious vasculitides [52] and
their primary target is the infected vessel wall. The question
relevant for classification and for therapy will be, if the
infectious microorganisms or the subsequent inflammatory process
are the main culprit for vessel destruction. The latter will
require anti-inflammatory, the former anti-infectious
treatment.
Table 8A Henoch-Schönlein Purpura, ACR criteria [53]
|
1. Palpable purpura (slightly raised “palpable” hemorrhagic skin
lesions, not related to thrombocytopenia)
|
|
2. Age ≤ 20 at disease onset (patient 20 years or younger at onset
of first symptoms)
|
|
3. Bowel angina (diffuse abdominal pain, worse after meals, or the
diagnosis of bowel ischemia, usually including bloody
diarrhoea)
|
|
4. Wall granulocytes on biopsy (histologic changes showing
granulocytes in the walls of arterioles or venules)
|
Table 9B Cutaneous leukocytoclastic angiitis, CHCC
definition [8]
|
• Isolated cutaneous leucocytoclastic angiitis without systemic
vasculitis or glomerulonephritis.
|
Table 8B Henoch-Schönlein Purpura, CHCC definition
[8]
|
• Vasculitis, with lgA-dominant immune deposits, affecting small
vessels (i.e. capillaries, venules, or arterioles).
|
|
• Typically involves skin, gut, and glomeruli, and is associated
with arthralgia or arthritis.
|
Table 9A Hypersensitivity vasculitis, ACR criteria
[39]
|
1. Age at disease onset >16 years (development of symptoms after
age 16)
|
|
2. Medication at disease onset (medication was taken at the onset
of symptoms that may have been a precipitating factor)
|
|
3. Palpable purpura (slightly elevated purpuric rash over one or
more areas of the skin; does not blanch with pressure and is not
related to thrombocytopenia
|
|
4. Maculopapular rash (flat and raised lesions of various sizes
over one or more areas of the skin)
|
|
5. Biopsy including arteriole and venule (histologic changes
showing granulocytes in a perivascular or extravascular
location)
|
Conclusions
The aim of this article is not to bring out yet another
classification system, but to use the common denominators of the
ACR and CHCC systems and to complete as well as update them,
focussing on the forms of vasculitis seen by dermatologists.
Since almost all forms of vasculitis can affect the skin, their
cutaneous symptoms may alarm patient and physician of an underlying
severe systemic form. We must therefore be capable of classifying
them clinically at least into one of the larger groups in order to
be able to take the right measures. Any form of vasculitis and LcV
of the skin has to be carefully monitored to exclude an underlying
systemic disease. If a severe course of a form of ANCA-associated
vascultis is suspected, then therapeutic measures should be
initiated before a more detailed diagnosis is established. When
cutaneous lesions are suggestive of PAN, then efforts must be made
to either detect or exclude visceral involvement, in order not to
overtreat a cutaneous PAN or to undertreat a systemic PAN. We have
put special emphasis on the various forms of LcV as they present
the most frequent vasculitis of the skin, and as they need to be
distinguished for prognostic reasons. As such a patient with LcV
will be diagnosed more deeply and repeatedly when the deposited
immune complexes contain primarily IgA (( figure 4 )) instead of only
IgG or IgM. In table 10( Table 10 ) we
have outlined diagnostic procedures as recently reviewed in more
detail [1]. We hope our classification will be helpful for clinical
use and for determining the extent of diagnostic procedures,
subsequent controls and of therapies.
Table 10 Stepwise procedure in patients with LcV of the
skin [1, 42]
|
Procedures taking into account patient’s history and clinical signs
as well as economic aspects
|
|
• Palpable purpura due to inflammatory infiltrate and hemorrhage
from necrotic vessels? → pathognomonic for LcV
|
|
• Histopathological analysis confirms the diagnosis, but is less
often required than direct immunofluorescence
|
|
• Direct immunofluorescence (to detect and identify perivascular
immunoglobulins)
|
|
- Perivascular IgA? → suspicion of HSP → repeated investigations
for renal or other systemic involvement, in adult age also
screening for malignant tumors [34]
|
|
• Bacteremia or sepsis should initially be excluded as a possible
cause for LcV
|
|
• Basic blood tests and procedures for investigation of systemic
involvement or causes of LcV:
|
|
- CRP, differential blood count (for hints to viral or bacterial
infection and for exclusion of thrombocytopenia or leukemia),
repeated urine analysis and hemoccult
|
|
- blood pressure
|
|
• Careful history for assessing possible systemic involvement or
causes of LcV
|
|
- passed illness (upper respiratory tract infections?)
|
|
- drug intake
|
|
- vaccinations or food intake
|
|
• In case of cold-induced lesions or chronic remitting disease
|
|
→ check for cryoglobulines
|
- – when negative → more complete work-up may become
necessary:
- complement levels, antibodies to nuclear antigens, to dsDNA,
Ro-SS/A or La- SS/B, ANCA, serology for hepatitis B or C,
antistreptolysin titer and paraproteins.
|
|
• In case of urticarial lesions (normo- or hypocomplementemic
urticarial vasculitis) or suspicion of Sjögrens’ syndrome or LE
|
|
→ standard search for antibodies to nuclear antigens, to dsDNA,
Ro-SS/A or La-SS/B plus complement levels
|
|
- When complement levels are reduced → search for antibodies to C1q
(→ syndrome of hypocomplementemic urticarial vasculitis with a high
and severe complication rate)
|
|
• In case there are signs and suspicion of systemic vasculitis →
ANCA, chest X ray, exclusion of sinusitis
|
|
• When there is livedo racemosa with nodules or even necrosis (no
LcV) → biopsy and investigation for systemic classical PAN
|
Acknowledgements
This article was supported by the grant BMBF Fkz 01 GM 0310 (C.S.).
The figures are from the Department of Dermatology and Allergology
of the University Hospital of Ulm and the Department of Dermatology
and Venerology of the University Hospital of Münster, Germany
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