Mikhail Valivach, MD, gives information on practical approaches to diagnosis of vasculitides.

1. Systematization and Diagnosis of
Vasculitides
Mikhail Valivach, MD
Pavlodar, Kazakhstan 2015

2. 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

3. 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.

4. 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).

5. An example of neutrophilic
inflammatory infiltrate
 Neutrophils and fragment of their decay (leukocytoclasis)
– nuclear “dust”

6. 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

7.  Cited from J. Charles Jennette Ronald J. Falk

8. 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.

9. CT. Large vessel vasculitis

10. Contrast angiography. Medium vessel
vasculitis
 CNS
vasculitis.
 Small
aneurisms and
beading of
medium size
arteries

11.  м
Renal arteries
Coronary arteries
Mesenterial arteries
Medium vessel vasculitides
Hepatic arteries

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

13. Vascular size and clinical manifestations
Small 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.
Цианоз
Изменения 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

14. 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

15. Let’s discuss primary pathogenetic mechanisms
 Cited from J. Charles Jennette Ronald J. Falk

16. Immune complexes
 Antigen-antibody complexes
 Potential antigens: bacteria,
fungi, parasites, viruses,
foods, medicines,
autoantigens, etc.
 Antibodies: IgG, IgM, IgA

17. Immune complex mediated vasculitis
 Cited from http://www.dentalnotebook.com/basics-hypersensitivity/

18. Histology of vasculitis. Angiocentric
inflammatory infiltrates

19. Immune complex deposits in vascular
walls
 Immune complex deposits
are detected by direct
immunofluorescence for
 IgG
 IgM
 IgA

20. 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.

21. Cryoglobulins
 Immunoglobulin
aggregates which are
formed at t < +37C.
 There are several types
of cryoglobulins
 Cryoglobulinemia can be
associated monoclonal
gammopathy and
rheumatoid factor.

22. 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.

23. 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

24. Causes of vasculitides: Goodpasture syndrome.
 мм
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)

25. Causes of vasculitides: ANCA
 ANCA - anti-
neutrophilic cytoplasmic
antibodies.
 ANCA are detected by
indirect
immunofluorescence or
ELISA.

26. 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.

27. Pathogenesis of ANCA- associated vasculitis
 Cited from http://unckidneycenter.org/kidney-health-
library/glomerular-disease/anca-vasculitis

28. 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.

29. 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.

30. Detection of granulomatous reaction
 Direct detection: Granulomas in
histology
 Indirect detection:
 Necroses in upper or lower
respiratory tract
 Necrotizing nodes in the lungs

31. 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.

32. 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.

33. 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.

34. 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).

35. 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.

36. Nosological diagnosis of primary
vasculitides

37. Small vessel vasculitides

38. 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).

39. 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).

40. 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).

41. 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.

42. 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.

43. 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.

44. 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.

45. 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.

46. 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.

47. 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.

48. Medium vessel vasculitides

49. 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).

50. 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.

51. 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.

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

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

54. Large vessel vasculitides

55. 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.

56. 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.

57. 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

58. 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

59. Thank you for your attention!