Systematization and Diagnosis of Vasculitides

Mikhail Valivach, MDPavlodar, Kazakhstan 2015

Preliminary notes

This is the second presentation on the subject. Here we do not discuss symptoms of vasculitides because we have

already described them in our first presentation. You can find this first presentation through yahoo.com using key

words valivach manifestations of vasculitides and pseudovasculitides In addition to these presentation we have prepared “A Quick

Reference Guide. Diagnosis of Vasculitides and Pseudovasculitides” which gives short rules how to apply theoretic knowledge into practical diagnosis.

You can find the guide through yahoo.com using key words valivach quick reference guide vasculitides and pseudovasculitides

Vasculitides Vasculitides can be defined as inflammatory

diseases of vessels. Vasculitides are usual manifestations of DCTD

and autoimmune diseases. Such vasculitides are called secondary.

Vasculitides without DCTD and autoimmune diseases are called primary.

We are discussing primary vasculitides in this presentation.

Biopsy with histology is the only evident method of vasculitis diagnosis.

Histologic criteria :

Perivascular (angiocentric) inflammatory infiltration.

Signs of vascular wall damage (necrosis, hemorrhages, changes of architecture, necrosis and atrophy in the supplied area).

An example of neutrophilic inflammatory infiltrate

Neutrophils and fragment of their decay (leukocytoclasis) – nuclear “dust”

Different classifications systematize vasculitides based on:

Size of affected vessels (small, medium, large). Primary pathogenetic mechanisms (ANCA, immune

complexes, anti-GBM). Special secondary inflammatory reactions

(granulomatous and eosinophilic). Distribution of vasculitis over organs of the body

(limited to one organ, special types of distribution). Severity of vascular damage (necrotising

vasculitides, hemorrhagic, urticarial). Severity of constitutional inflammatory reactions

(fever, weight loss). Age of onset

Cited from J. Charles Jennette Ronald J. Falk

How to determine the size of affected vessels?

Biopsy with histology: Only small size vessels are available and rarely medium size.

Imaging methods: Large and medium size vessels are available.

Based on clinical manifestations.

Various combinations of these methods are used in practice.

CT. Large vessel vasculitis

Contrast angiography. Medium vessel vasculitis

CNS vasculitis.

Small aneurisms and beading of medium size arteries

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Renal arteries

Coronary arteries

Mesenterial arteries

Medium vessel vasculitides

Hepatic arteries

A small vessel vasculitis shows a pneumonia-like chest x-ray picture

Vascular size and clinical manifestationsSmall vessels Medium vessels Large vessels

Skin Maculopapular rash (fixed palpable erythema). Palpable purpura. Erosions, superficial ulcers and crusting. Atrophy blanche.

Livedo reticularis. Necroses, including distal necroses. Ulcers.

ЦианозИзменения цвета конечностей

GI Inflammation and erosions of mucous membranes. GI hemorrhages.

Abdominal pains. Intestinal perforations.

Ischemic abdominal pains (abdominal angina). Intestinal infarctions.

Lungs Chest imaging: pneumonia-like shadows, ground-glass opacity, cavitating and noncavitating nodules

Wedge shaped opacities on chest x-ray (like pulmonary embolism)

Scanty lung pattern. Respiratory failure.

Kidneys Hematuria with red blood cell casts. Proteinuria. Renoparenchymal hypertension.

Hematuria without red blood cell casts. Dull pain. Vasorenal and/or renoparenchimal hypertension.

Vasorenal hypertension. No blood and no protein in urine.

Nervous system

Brain lesions do not correspond to vascular beds. Poly- and mononeuropathies.

Brain lesions correspond to vascular beds or their segments.

Signs of affection of common, external, internal carotid or vertebral artery.

Muscles Myalgias Myalgias Intermittent claudication

Primary pathogenetic mechanisms:

Immune complex deposition. Anti- glomerular basement membrane

antibody. Goodpasture syndrome. Anti-Neutrophil Cytoplasmic Antibody (ANCA). Endothelial infections. Note: with purpose to

avoid contradiction of existing classifications it is better to call these diseases endotheliitis but not vasculitis

Let’s discuss primary pathogenetic mechanisms

Cited from J. Charles Jennette Ronald J. Falk

Immune complexes

Antigen-antibody complexes

Potential antigens: bacteria, fungi, parasites, viruses, foods, medicines, autoantigens, etc.

Antibodies: IgG, IgM, IgA

Immune complex mediated vasculitis

Cited from http://www.dentalnotebook.com/basics-hypersensitivity/

Histology of vasculitis. Angiocentric inflammatory infiltrates

Immune complex deposits in vascular walls

Immune complex deposits are detected by direct immunofluorescence for

IgG IgM IgA

Immune complexes in paraproteinemias

Parapoteins can aggregate and behave like immune complexes:

Cryoglobilins (aggregation at t < +37C) Monoclonal gammopathies (some MGs have

properties of cryoglobulins). Aggregated paraproteins can form deposits in

vascular walls and cause the same reactions as immune complexes.

Large aggregates can also cause small vessel embolism.

Cryoglobulins

Immunoglobulin aggregates which are formed at t < +37C.

There are several types of cryoglobulins

Cryoglobulinemia can be associated monoclonal gammopathy and rheumatoid factor.

Monoclonal gammopathies Immunoglobulins

produced by a plasma cell monoclone).

These can be plasma cell lymphomas, leukemia and preleukemic conditions

Patients with MG should be consulted by hemathologist.

MG is detected by plasma protein electrophoresis.

This test is mandatory in small vessel vascultis.

Light and heavy chain diseases There are light

and heavy chain diseases which are monoclonal gammopathies characterized by production of abnormal, structurally incomplete, immunoglobulins.

Cited from http://csckalvarayanhills.org.in/14/immunoglobulin-light-chain

Causes of vasculitides: Goodpasture syndrome.

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Goodpasture syndrome (GPS; antiglomerular basement antibody disease, or anti-GBM disease) is an autoimmune disease in which antibodies attack the basement membrane in lungs and kidneys, leading to bleeding from the lungs and kidney failure (https://en.wikipedia.org/wiki/Goodpasture_syndrome)

Causes of vasculitides: ANCA

ANCA - anti-neutrophilic cytoplasmic antibodies.

ANCA are detected by indirect immunofluorescence or ELISA.

ANCA ANCA are autoantobodies against cytoplasmic

antigens of neurtophils. These antigenes are two enzymes: proteinase-

3 and myeloperoxidase. Antibodies against myeloperoxidase are called

p-ANCA, and antibodies against proteinase-3 are called c-ANCA.

ANCA do not damage but stimulate neutrophils.

Activated neutrophils attack walls of small vessels leading to development of vasculitis.

Pathogenesis of ANCA- associated vasculitis

Cited from http://unckidneycenter.org/kidney-health-library/glomerular-disease/anca-vasculitis

Special secondary inflammatory reactions

In immune complex and ANCA – associated vasculitides inflammation is connected with neutrophilic infiltration that is followed by lymphohistiocytic infiltration.

In some people a special secondary inflammatory reaction develops which can be:

- granulomatous or - eosinophilic. These secondary reactions are important

diagnostic criteria of two forms of vasculitides.

Detection of eosinophilic reaction

Histology: perivascular eosinophilic granulomas

OR > 25% of eosinophils among

inflammatory cells in sputum OR Stable blood eosinophilia

>10% in repeated tests.

Detection of granulomatous reaction Direct detection: Granulomas

in histology

Indirect detection:

Necroses in upper or lower respiratory tract

Necrotizing nodes in the lungs

Distribution of vasculitis over organs of the body

The same pathogenetic mechanism can affect vessels of different organs (for example only renal glomeruli, or skin and lungs, etc.). In accordance to modern classifications these will be different forms of vasculitides.

In some nosologies organ distribution is a more important diagnostic criteria than pathogenetic mechanisms. For example, Kawasaki and Behcet diseases, vasculitis limited to skin, etc.

Monoorganic vasculitides as nosologies Vasculitis limited to skin is

one nosology independently on pathogenesis (excluding monoclonal gammopathy).

Isolated CNS vasculitis (excluding monoclonal gammopathy).

Primary glomerulonephritis (vasculitis limited to renal glomeruli). Excluding monoclonal gammopathy.

Combined damage of renal glomeruli and lung capillaries

Can be present in Goodpasture syndrome and in many other vasculitides.

Unlike other vasculitides, in Goodpasture syndrome one can find anti- glomerular basement membrane antibodies.

Vasculitides are multifactorial diseases Clinical picture of vasculitis depends on

the following relatively independent factors:

Size of affected vessels (small, medium, large). Primary pathogenetic mechanisms (ANCA,

immune complexes, anti-GBM). Special secondary inflammatory reactions

(granulomatous and eosinophilic). Distribution of vasculitis over organs of the

body (limited to one organ, special types of distribution).

Classifications of vasculitides

At present the following partly overlapping classifications are used:

Criteria of American College of Rheumatology Definitions of Chapel Hill Consensus Conference Diagnostic and Classification Criteria for Primary

Systemic Vasculitis (ACR/EULAR) NOTE: These classifications are applicable only

to primary vasculitides. Thus, DCTD and other autoiimmune diseases should be first excluded.

Nosological diagnosis of primary vasculitides

Small vessel vasculitides

Chapel Hill definitions for vasculitides Microscopic polyangiitis (MPA) Necrotizing vasculitis, with few or no immune

deposits, predominantly affecting small vessels (i.e., capillaries, venules, or arterioles). Necrotizing arteritis involving small and medium arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation is absent.

Contradictions with EULAR: ANCA-positivity is not mentioned as a mandatory criterion. Severity of vascular damage is used as a criterion (necrotizing).

Chapel Hill definitions for vasculitides Granulomatosis with polyangiitis

(Wegener's) (GPA) Necrotizing granulomatous inflammation usually

involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly small to medium vessels (e.g., capillaries, venules, arterioles, arteries and veins). Necrotizing glomerulonephritis is common.

Contradictions with EULAR: ANCA-positivity is not mentioned as a mandatory criterion. Severity of vascular damage is used as a criterion (necrotizing).

Chapel Hill definitions for vasculitides Eosinophilic granulomatosis with

polyangiitis (Churg-Strauss) (EGPA) Eosinophil-rich and necrotizing granulomatous

inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels, and associated with asthma and eosinophilia. ANCA is more frequent when glomerulonephritis is present.

Contradictions with EULAR: Severity of vascular damage is used as a criterion (necrotizing).

Chapel Hill definitions for vasculitides

IgA vasculitis (Henoch-Schönlein) (IgAV): Vasculitis, with IgA1-dominant immune

deposits, affecting small vessels (predominantly capillaries, venules, or arterioles). Often involves skin and gastrointestinal tract, and frequently causes arthritis. Glomerulonephritis indistinguishable from IgA nephropathy may occur.

Contradictions with EULAR: No contradictions.

Chapel Hill definitions for vasculitides Cryoglobulinemic vasculitis (CV):

Vasculitis with cryoglobulin immune deposits affecting small vessels (predominantly capillaries, venules, or arterioles) and associated with serum cryoglobulins. Skin, glomeruli, and peripheral nerves are often involved.

Contradictions with EULAR: No contradictions.

Chapel Hill definitions for vasculitides

Immune complex vasculitis Vasculitis with moderate to marked vessel

wall deposits of immunoglobulin and/or complement components predominantly affecting small vessels (i.e., capillaries, venules, arterioles, and small arteries). Glomerulonephritis is frequent.

Contradictions with EULAR: ANCA-negativity is not mentioned as a mandatory criterion.

Chapel Hill definitions for vasculitides

Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis)

Vasculitis accompanied by urticaria and hypocomplementemia affecting small vessels (i.e., capillaries, venules, or arterioles), and associated with anti-C1q antibodies. Glomerulonephritis, arthritis, obstructive pulmonary disease, and ocular inflammation are common.

Contradictions with EULAR: No contradictions.

Chapel Hill definitions for vasculitides Anti–glomerular basement membrane (anti-

GBM) disease

Vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with GBM deposition of anti-GBM autoantibodies. Lung involvement causes pulmonary hemorrhage, and renal involvement causes glomerulonephritis with necrosis and crescents.

Contradictions with EULAR: No contradictions.

The American College of Rheumatology 1990 criteria

Hypersensitivity Vasculitis Note (M.Valivach): It is supposed that this vasculitis is caused by reaction

to a foreign antigen (medicine, infection, food, etc.) and is mediated by deposition of immune complexes. In most cases it is not possible to determine causal antigen. This vasculitis corresponds to immune complex vasculitis (Chapel Hill).

Three of the following five criteria are required to meet American College of Rheumatology (ACR) classification criteria for hypersensitivity vasculitis:

Age at disease onset older than 16 years. Medication at disease onset as a precipitating factor. Palpable purpura. Maculopapular rash. Biopsy specimen showing granulocytes around an arteriole and venule. Contradictions with EULAR: ANCA negativity not mentioned. Age is

used as a criterion. Detection of IgG or IgM immune deposits is not required for diagnosis. Not mentioned differential diagnosis with paraproteinemic and hypocomplementemic vasculitides.

Vasculitis caused by monoclonal gammopathy.

No conventional definition. Small vessel vasculitis that can be both mono- and

poliorganic. Complement activity and ANCA have no significance for diagnosis.

Monoclonal immunoglobulin in the blood is the main criterion.

Hemathologist consultation for differential diagnosis between lymphomas, leukemias, MG of undetermined significance.

Medium vessel vasculitides

Chapel Hill definitions for vasculitides Polyarteritis nodosa (PAN): Necrotizing arteritis of medium or small arteries without

glomerulonephritis or vasculitis in arterioles, capillaries, or venules, and not associated with antineutrophil cytoplasmic antibodies (ANCAs).

NOTE: I would suggest to define PAN as a vasculitis of predominantly medium size vessels without affection of large vessels, ANCA – negative, without monoclonal gammopathy.

EULAR does not recommend to use severity of damage as a diagnostic criterion (necrotizing).

Chapel Hill definitions for vasculitides

Kawasaki disease (KD): Arteritis associated with the mucocutaneous

lymph node syndrome and predominantly affecting medium and small arteries. Coronary arteries are often involved. Aorta and large arteries may be involved. Usually occurs in infants and young children.

NOTE: Coronary aneurisms can develop as a long-term complication.

Criteria of acute Kawasaki syndrome Presence of at least four of the following five principal features†: Changes in extremities: these changes are distinctive and acutely include

redness, swelling and, sometimes, induration of the hands and feet. One to three weeks after the onset of fever, desquamation of the fingers and toes occurs. Approximately one to two months after the onset of fever, Beau's lines (white lines across the fingernails) may appear.

Polymorphic exanthem: the skin eruption involves the trunk and extremities and may have several forms, including urticarial exanthem, a morbilliform maculopapular eruption (occasionally with target lesions) or a diffuse scarlatiniform rash. Bullae and vesicles are not seen. The rash usually appears within five days after the onset of fever.

Bilateral conjunctival injection: the bulbar conjunctivae, rather than the palpebral or tarsal conjunctivae, are involved. Typically, the limbic region is spared. The conjunctival injection is not associated with an exudate and is usually painless.

Changes in the lips and oral cavity: these changes include strawberry tongue, redness and cracking of the lips, and erythema of the oropharyngeal mucosa. Ulcerative lesions are not seen.

Cervical lymphadenopathy (at least one lymph node with a diameter of 1.5 cm or greater): the lymphadenopathy is usually unilateral, with firm and slightly tender nodes.

Exclusion of other diseases with similar findings.

Cited from http://nursingmnemonics.blogspot.com/2012/07/kawasaki-syndrome.html

Cited from http://www.nejm.org/doi/full/10.1056/NEJM199511233332105

Large vessel vasculitides

Chapel Hill definitions for vasculitides

Giant cell arteritis (GCA). Temporal arteriitis:

Arteritis, often granulomatous, usually affecting the aorta and/or its major branches, with a predilection for the branches of the carotid and vertebral arteries. Often involves the temporal artery. Onset usually in patients older than 50 years and often associated with polymyalgia rheumatica.

Chapel Hill definitions for vasculitides

Takayasu arteritis (TAK): Arteritis, often granulomatous, predominantly affecting the aorta and/or its major branches. Onset usually in patients younger than 50 years.

Additional material

I have made a presentation on an interesting case of Takayasu’s arteriitis at an international seminar in Salzburg.

You can find video of this short presentation on youtube.com using key words valivach salzburg takayasu

Practical diagnosis of vasculitides

We have created a quick reference guide on vasculitides and pseudovasculitides which occupies two sides of A4 sheet.

You can find the guide through yahoo.com using key words valivach quick reference guide vasculitides and pseudovasculitides

Dear colleagues, with questions and suggestions you can address to Mikhail Valivach valivach@mail.ru

Thank you for your attention!