Update on vasculitis

Update on vasculitisUpdate on vasculitis

บุ�ญธร ตั�นวรเศรษฐี�บุ�ญธร ตั�นวรเศรษฐี�10 july 200910 july 2009

OutlineOutline

DefinitionDefinition ClassificationClassification PathogenesisPathogenesis Clinical featuresClinical features TreatmentTreatment focus on vasculitic syndromes more likely to be focus on vasculitic syndromes more likely to be

presented to allergist/immunologist in outpatient presented to allergist/immunologist in outpatient settingsetting

DefinitionDefinition

inflammation of the blood vesselsPathology:destruction of the vessel wallHistology:fibrinoid necrosisnecrotizing vasculitis

CClassificationlassification

Dominant vessel involved

Primary Secondary

Large arteries Giant cell arteritis

Takayasu arteritis

Aortitis associated with RA

Infection (e.g. syphilis, tuberculosis)

Medium arteries Classical PAN

Kawasaki disease

HBV-associated PAN

Small vessels and medium arteries

Wegener’s granulomatosis

Churg–Strauss syndrome

Microscopic polyangiitis

Vasculitis secondary to RA, SLE, Sjogren’s syndrome

Drugs (PTU,hydralazine)

Infection (e.g. HIV)

Small vessels (leukocytoclastic)

Henoch–Schonlein purpura

Cutaneous leucocytoclastic Angitis

Mixed essential cryoglobulinaemia

Drugs (sulfa,penicillin,thiazide)

Infection

HCV-induced cryoglobulinaemia

Best Practice & Research Clinical Rheumatology 23 (2009) 429–443Best Practice & Research Clinical Rheumatology 23 (2009) 429–443

CClassificationlassificationSize of dominant vessel affected

Granulomatous Non-Granulomatous

Large Giant cell arteritis

Takayasu arteritis

Medium Classical PAN

Kawasaki disease

Small Wegener’s granulomatosis

Churg–Strauss syndrome

Microscopic polyangiitis

Henoch–Schonlein purpura

Cutaneous leucocytoclastic Angitis

Mixed essential cryoglobulinaemia

Lancet 1997; Lancet 1997; 349: 553-58349: 553-58


Best Practice & Research Clinical Rheumatology Best Practice & Research Clinical Rheumatology Vol. 15, No. 2, pp. 259±279, 2001Vol. 15, No. 2, pp. 259±279, 2001

CClassificationlassification Antibody mediated

CSS MPA WG

Immune complex mediated CV Drug-induced vasculitis HSP Hepatitis B–associated PAN

Pathogenic T-cell response mediated CSS GCA TAK WG

J ALLERGY CLIN IMMUNOL JUNE 2009J ALLERGY CLIN IMMUNOL JUNE 2009


Dominant vessel Corticosteroids alone

Cyclophosphamide

and corticosteroids

Other treatments

Large arteries ++++++ -- ++

Medium arteries ++ ++++ ++++

Small vessels and medium arteries

++ ++++++ ++

Small vessels ++ +/-+/- ++++

Best Practice & Research Clinical Rheumatology 23 (2009) 429–443Best Practice & Research Clinical Rheumatology 23 (2009) 429–443

Mechanisms of vascular Mechanisms of vascular inflammation and remodellinginflammation and remodelling

2009 British Society for Immunology, 2009 British Society for Immunology, Clinical and Experimental Immunology, Clinical and Experimental Immunology, 156: 395–404156: 395–404


(a) Viable endothelial cells express P-selectin (a) Viable endothelial cells express P-selectin after activation. P-selectin recognition prompts after activation. P-selectin recognition prompts leucocyte tethering and rolling,resulting in integrin leucocyte tethering and rolling,resulting in integrin activation with firm adhesion and eventual trans-activation with firm adhesion and eventual trans-endothelial migration. (b) Injured endothelial cells endothelial migration. (b) Injured endothelial cells fail to express the signals required for leucocyte fail to express the signals required for leucocyte migration. Recruited platelets express P-selectin migration. Recruited platelets express P-selectin and, besides limiting bleeding, substitute and, besides limiting bleeding, substitute endothelial cells in delivering signals to flowing endothelial cells in delivering signals to flowing inflammatory leucocytes. (c) A neutrophil can be inflammatory leucocytes. (c) A neutrophil can be identified easily on an atherosclerotic lesion in a identified easily on an atherosclerotic lesion in a damaged human vessel, based on nuclear damaged human vessel, based on nuclear characteristics (blue colour, Hoechst) and on the characteristics (blue colour, Hoechst) and on the expression of the CD66b (red). Endothelial cells expression of the CD66b (red). Endothelial cells and activated platelets express P-selectin (pink). and activated platelets express P-selectin (pink). The prototypic tissue pentraxin PTX3 (green) is The prototypic tissue pentraxin PTX3 (green) is expressed within the lesion at extracellular sites.expressed within the lesion at extracellular sites.

The interaction between activated platelets and The interaction between activated platelets and flowing leucocytes yields heteroaggregates in the flowing leucocytes yields heteroaggregates in the circulating blood, which are typical of several circulating blood, which are typical of several inflammatory diseases.(a,b,c) inflammatory diseases.(a,b,c) Confocal images of platelet–neutrophil hetero-Confocal images of platelet–neutrophil hetero-aggregates in whole blood samples from a patient aggregates in whole blood samples from a patient with acute myocardial infarction. Glycoprotein Ib with acute myocardial infarction. Glycoprotein Ib expression (red) reveals platelets, the CD66b expression (red) reveals platelets, the CD66b marker (green) neutrophils. Hoechst (blue) was marker (green) neutrophils. Hoechst (blue) was used to counterstain nuclei. (d) Electron used to counterstain nuclei. (d) Electron microscopy of the interaction between neutrophil microscopy of the interaction between neutrophil and platelet membranes.and platelet membranes.

(a)(a) (b)(b) (c)(c)

((d)d)


Pathogenesis of AASVPathogenesis of AASV

NEPHROLOGY 2009; 14, 26–32NEPHROLOGY 2009; 14, 26–32

Schematic representation of the neutrophil Schematic representation of the neutrophil responses that are putatively involved in responses that are putatively involved in the the pathogenesis of ANCA-associated small pathogenesis of ANCA-associated small vessel vasculitis. (vessel vasculitis. (A) Proinflammatory A) Proinflammatory cytokines and chemokines cytokines and chemokines (e.g. tumor (e.g. tumor necrosis factor) that are released as a result of necrosis factor) that are released as a result of local or systemic infection cause upregulation local or systemic infection cause upregulation of the expression of endothelial adhesion of the expression of endothelial adhesion molecules (e.g. selectins, intercellular molecules (e.g. selectins, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 and vascular cell adhesion molecule 1), and prime neutrophils. adhesion molecule 1), and prime neutrophils. ((B) Neutrophil priming causes B) Neutrophil priming causes upregulation of upregulation of the expression of neutrophil the expression of neutrophil adhesion molecules (CD11b) and adhesion molecules (CD11b) and translocation of the ANCA antigens from translocation of the ANCA antigens from their lysosomal compartments to the cell their lysosomal compartments to the cell surface. (surface. (C) Engagement of dimers of the C) Engagement of dimers of the antigen-binding portion antigen-binding portion of ANCA with of ANCA with ANCA antigens on the cell surface, and ANCA antigens on the cell surface, and interaction of the Fc part of the antibody with interaction of the Fc part of the antibody with Fc receptors, activates eutrophils and causes Fc receptors, activates eutrophils and causes increased transmigration and adherence of increased transmigration and adherence of neutrophils to vessel walls. (neutrophils to vessel walls. (D) ANCA-D) ANCA-mediated neutrophil activation also mediated neutrophil activation also triggers production of reactive oxygen triggers production of reactive oxygen radicals radicals and possibly causes neutrophil and possibly causes neutrophil degranulation. The consequent release of degranulation. The consequent release of proteolytic enzymes leads to vasculitis. proteolytic enzymes leads to vasculitis.

KALLENBERG KALLENBERG ET AL.ET AL. NATURE CLINICAL PRACTICE RHEUMATOLOGY NATURE CLINICAL PRACTICE RHEUMATOLOGY DECEMBER 2006 VOL 2 NO 12 DECEMBER 2006 VOL 2 NO 12

The role The role of ANCA and cytokines in the of ANCA and cytokines in the pathogenesis of neutrophil-pathogenesis of neutrophil-mediatedmediatedvascular injury. Infection or other vascular injury. Infection or other inflammatory stimulus leads to production inflammatory stimulus leads to production of proinflammatory cytokines (i.e., IL-1, of proinflammatory cytokines (i.e., IL-1, TNF-a, and IL-8), which induce resting TNF-a, and IL-8), which induce resting neutrophils to express proteinase-3 on their neutrophils to express proteinase-3 on their cell surface. IL-1 and TNF-a also induce cell surface. IL-1 and TNF-a also induce neutrophils and endothelial cells to increase neutrophils and endothelial cells to increase their expression of adhesion molecules, their expression of adhesion molecules, leading to adhesion of activatedleading to adhesion of activatedneutrophils to the vascular endothelium. neutrophils to the vascular endothelium. Circulating ANCA binds to membrane-Circulating ANCA binds to membrane-associated proteinase-3 and the FcyRlla associated proteinase-3 and the FcyRlla receptor inducing neutrophil degranulation receptor inducing neutrophil degranulation and generation of oxygen radicals, which and generation of oxygen radicals, which results in endothelial cell injury and results in endothelial cell injury and inflammationinflammation

Medical Clinics Of North America Volume 81 Number 1 January 1997Medical Clinics Of North America Volume 81 Number 1 January 1997

Best Practice & Research Clinical Rheumatology Vol. 15, No. 2, pp. 259±279, 2001Best Practice & Research Clinical Rheumatology Vol. 15, No. 2, pp. 259±279, 2001

Gateway–receptor interaction model. 1. In Wegener’s granulomatosis (WG), expression of PR3 in the extracellular space is increased. Gateway–receptor interaction model. 1. In Wegener’s granulomatosis (WG), expression of PR3 in the extracellular space is increased. PR3 stimulates the expression of PAR-2 on DC. 2. PR3 activates PAR-2 resulting in maturation of DC, as indicated by expression of PR3 stimulates the expression of PAR-2 on DC. 2. PR3 activates PAR-2 resulting in maturation of DC, as indicated by expression of CD80, CD83, CD86, and HLA-DR. 3. These PR3-maturated DCs stimulate CD4+ T cells to generate increasedCD80, CD83, CD86, and HLA-DR. 3. These PR3-maturated DCs stimulate CD4+ T cells to generate increasedexpression of IFN-γ. 4. expression of IFN-γ. 4. Expression of IFN-γ favors the development of a granulomatous inflammation as seen in WG. 5 Hypothetically, chronic T Expression of IFN-γ favors the development of a granulomatous inflammation as seen in WG. 5 Hypothetically, chronic T cell activation by PR3-maturated DCs may finally promote the development of B-cells towards ANCA-producing plasma cell activation by PR3-maturated DCs may finally promote the development of B-cells towards ANCA-producing plasma cells.cells.

Clinic Rev Allerg Immunol (2008) 34:300–306Clinic Rev Allerg Immunol (2008) 34:300–306

Adhesion MoleculesAdhesion Molecules

Best Practice & Research Clinical Best Practice & Research Clinical Rheumatology Vol. 15, No. 2, pp. Rheumatology Vol. 15, No. 2, pp. 259-279, 2001259-279, 2001

Chemokine and receptorsChemokine and receptors

Best Practice & Research Best Practice & Research Clinical Rheumatology Vol. 15, Clinical Rheumatology Vol. 15, No. 2, pp. 259-279, 2001No. 2, pp. 259-279, 2001

CytokineCytokineCytokine Abbreviatio

nCellular Source Biologic Effects

Interferon-gamma

IFN T cells, NK cells Increases expression of MHC class I and II molecules;macrophage activation; antiviral activity

Interleukin-I IL-1 Macrophages,neutrophils,

endothelial cells, T and B cells NK cells,fibroblasts, smooth muscle cells

Acts as costimulant for T and B

cell proliferation, activates

endothelial cells, induces

hepatic synthesis of acute

phase proteins, endogenous

pyrogen activity, increases

adhesion molecule expression

on endothelial cells

Interleukin-2 IL-2 T cells Induces proliferation and

differentiation of T cells and B

cells; stimulates cytotoxicity of

NK cells

Interleukin-6 IL-6 T cells, endothelial cells,

macrophages,

fibroblasts

Promote growth and differentiation of T and B cell;induce hepatic synthesis of acute phase protein,endogenous pyrogen activity

CytokineCytokineCytokine Abbreviatio

nCellular Source Biologic Effects

Interleukin-8 IL-8 T cells, NK cells Increases expression of MHC class I and II molecules;macrophage activation; antiviral activity

Tumor necroti factor alpha

TNF-α Macrophages,neutrophils,

endothelial cells, T and B cells NK cells,fibroblasts, smooth muscle cells

Acts as costimulant for T and B

cell proliferation, activates

endothelial cells, induces

hepatic synthesis of acute

phase proteins, endogenous

pyrogen activity, increases

adhesion molecule expression

on endothelial cells

Platelet-derived growth factor

PDGF T cells Induces proliferation and

differentiation of T cells and B

cells; stimulates cytotoxicity of

NK cells

T cells, endothelial cells,

macrophages,

fibroblasts

Promote growth and differentiation of T and B cell;induce hepatic synthesis of acute phase protein,endogenous pyrogen activity

Clinical signs ( primary systemic vasculitis )

Fever of unknown origin Unexplained migratory polyarthritis Mononeuritis multiplex Rapidly progressive glomerulonephritis Palpable purpura Diffuse alveolar hemorrhage Unexplained infarction in multiple vascular territo

ries Unexplained multisystem disease


Giant cell arteritisGiant cell arteritis

“Temporal arteritis” Granulomatous large-vessel vasculitis Older than 50 years Headache ( ‘‘sinus’’ headache ) Fever, jaw or tongue claudication, and scalp tenderne

ss Polymyalgia rheumatica ( 40-50%) Blindness from optic nerve ischemia (15- 20%) ,diplo

pia and ptosis Life-threatening aortic rupture or dissection


Giant cell arteritisGiant cell arteritis Nodularity, tenderness or absent pulsations of the tem

poral arteries and other involved vessels Bruits, and asymmetric extremity blood pressure mea

surements ESR usually increased ,ncnc anemia, thrombocytosis,

and increased alk. phosphatase levels. Temporal artery biopsy (TAB) : granulomatous infla

mmation of the media and adventitia, with histiocytes and mononuclear cells, giant cells, irregular fragmentation of the internal elastic lamina, neointimal proliferation, and sometimes luminal thrombosis (25%). positive 60-80%positive 60-80%

Contralateral TAB if first biopsy negativeJ ALLERGY CLIN IMMUNOL JUNE 2009J ALLERGY CLIN IMMUNOL JUNE 2009

Giant cell arteritisGiant cell arteritis Prednisone at 40 to 60 mg/d Immediate symptomatic benefit and reduction in the risk

of blindness (1%) IV methylprednisolone (1 g for 3 days) in patients with a

cute vision loss ( protect unaffected eye ) Baby aspirin prevent ischemic complications MTX and Infliximab not shown benefit Relapse > 75% 40-50% unable to taper prednisone Acute mortality is uncommon Late mortality :rupture or dissection of aortic aneurysms


Takayasu arteritisTakayasu arteritis Granulomatous large-vessel vasculitis Affects aorta, its main branches, and pulmonary a. Predominantly in young women Headaches and dizziness Vascular hypoperfusion :limb claudication, double visi

on or rapid decrease in VA,chest pain,CHF,TIAor stroke

HT , bruits (carotid or subclavian) diminished pulses, diminished pulses, asymmetric BP, AR, and arterial tendernessasymmetric BP, AR, and arterial tenderness

Glucocorticoids ,once-weekly MTX ,surgical revascularization (while clinically inactive)


Takayasu arteritisTakayasu arteritis

FIG 1. Magnetic resonance angiography in a patient with TAK showing multiple stenoses at the origin of both common carotid arteries and the left subclavian artery.


Wegener granulomatosisWegener granulomatosis

Granulomatous, necrotizing, small and medium vesselGranulomatous, necrotizing, small and medium vessel Involves upper,lower airways, and kidneysInvolves upper,lower airways, and kidneys Any age (40-55 yrs.) Men and women equallyAny age (40-55 yrs.) Men and women equally Frequency of 3 per 100,000 personsFrequency of 3 per 100,000 persons Upper airways symptoms (recurrent or nonresolving sinusitis, Upper airways symptoms (recurrent or nonresolving sinusitis,

nosebleeds, nasal crustingnosebleeds, nasal crusting Sinus pain, epistaxis, persistent otitis media with effusion or Sinus pain, epistaxis, persistent otitis media with effusion or

decreased hearing, and cartilage ischemia with nasal septal decreased hearing, and cartilage ischemia with nasal septal perforation (saddle nose deformity) subglottic stenosis. perforation (saddle nose deformity) subglottic stenosis.

Single or multiple cavitating/noncavitating nodules or diffuse Single or multiple cavitating/noncavitating nodules or diffuse alveolar hemorrhagealveolar hemorrhage


Wegener granulomatosisWegener granulomatosis Microscopic hematuria, proteinuria, and rapidly progressive Microscopic hematuria, proteinuria, and rapidly progressive

RFRF Skin rash, migratory arthritisSkin rash, migratory arthritis Ocular involvement (scleritis, corneal ulceration,orbital dis.)Ocular involvement (scleritis, corneal ulceration,orbital dis.) Mononeuritis multiplex or CNS involvement with or without Mononeuritis multiplex or CNS involvement with or without

pachymeningitispachymeningitis Risk of venous thrombosis (DVT,PE) mechanism unclearRisk of venous thrombosis (DVT,PE) mechanism unclear ANCA (180pt., 96%with severe dis.,83%with limited dis.)ANCA (180pt., 96%with severe dis.,83%with limited dis.) Lung biopsy yield 91% of casesLung biopsy yield 91% of cases Upper airway biopsy yield only 21%of casesUpper airway biopsy yield only 21%of cases Renal biopsy:focal, segmental necrotizing, crescentic Renal biopsy:focal, segmental necrotizing, crescentic

glomerulonephritis with few to no immune complexes glomerulonephritis with few to no immune complexes


KALLENBERG KALLENBERG ET AL. DECEMBER 2006 VOL 2 NO 12ET AL. DECEMBER 2006 VOL 2 NO 12


Active severe organ- or life-threatening (2 mkd CYC and 1 mkd Active severe organ- or life-threatening (2 mkd CYC and 1 mkd prednisone) 91% improvement ,75% complete remission, and prednisone) 91% improvement ,75% complete remission, and 80%survival 80%survival

Fulminant disease (1 g/d iv methylprednisolone 3d and 3 to 4 Fulminant disease (1 g/d iv methylprednisolone 3d and 3 to 4 mg/kg/d iv or oral CYC 3 d,reduced to 2 mg/kg/d after 4 weeks, mg/kg/d iv or oral CYC 3 d,reduced to 2 mg/kg/d after 4 weeks, if improvement, tape prednisone 6-9 mo.if improvement, tape prednisone 6-9 mo.

Maintainance at least 2 yrs.(MTX 15-25mg/wk,AZA 2 Maintainance at least 2 yrs.(MTX 15-25mg/wk,AZA 2 mkd),MMF,leflunomide (small data )mkd),MMF,leflunomide (small data )

Nonsevere (weekly MTX+daily prrednisolone)=> higher of Nonsevere (weekly MTX+daily prrednisolone)=> higher of relapse raterelapse rate

TMP-SMZ reduce only relapses upper airways , prophylaxis for TMP-SMZ reduce only relapses upper airways , prophylaxis for Pneumocystis jiroveci infectionPneumocystis jiroveci infection



Plasma exchange additional in severe renal vasculitis Plasma exchange additional in severe renal vasculitis (Cr>5.8mg/dl) reduced risk of progression to ESRD by 24% (Cr>5.8mg/dl) reduced risk of progression to ESRD by 24% over 1 yearover 1 year

Etanercept (no benefit)Etanercept (no benefit) Infliximab (absence of randomized control trial )Infliximab (absence of randomized control trial ) Rithuximab (being studied)Rithuximab (being studied)



FIG 2. WG involving the lungs with pulmonary nodules.



FIG 3. WG involving the lungs with diffuse alveolar hemorrhage andpulmonary nodules



FIG 4. WG involving the right orbit and paranasal sinuses, resulting in anorbital mass and enophthalmos


Microscopic polyangiitisMicroscopic polyangiitis

Nongranulomatous necrotizing small-vessel vasculitis,few or no Nongranulomatous necrotizing small-vessel vasculitis,few or no immune deposits immune deposits

More common in male , average age of onset is 50 yearsMore common in male , average age of onset is 50 years Persistent cough with or without hemoptysisPersistent cough with or without hemoptysis Kidneys (79%), lungs (12- 29%), joints (65- 72%), skin (44- 58%), Kidneys (79%), lungs (12- 29%), joints (65- 72%), skin (44- 58%),

GI tract (32- 58%), peripheral nerves (14- 36%)GI tract (32- 58%), peripheral nerves (14- 36%) Pulmonary pathology shows capillaritis and absence of linear IF, Pulmonary pathology shows capillaritis and absence of linear IF,

differentiating from goodpasture syndrome differentiating from goodpasture syndrome Renal histology is similar to WG Renal histology is similar to WG Severe disease (lung, kidney, or nerve) 2 mkd oral CYC and Severe disease (lung, kidney, or nerve) 2 mkd oral CYC and

1 mkd prednisone 3- 6 mo., Followed by weekly MTX or daily 1 mkd prednisone 3- 6 mo., Followed by weekly MTX or daily AZAAZA


Churg-Strauss syndromeChurg-Strauss syndrome asthma, fever, hypereosinophilia, systemic vasculitisasthma, fever, hypereosinophilia, systemic vasculitis Prevalence 3 per million , all ages but rare in children and Prevalence 3 per million , all ages but rare in children and

adolescents and occurs equally between sexesadolescents and occurs equally between sexes recurrent allergic rhinitis, difficult-to-treat asthma, nonresolving recurrent allergic rhinitis, difficult-to-treat asthma, nonresolving

‘‘pneumonia’’/pulmonary infiltrates, or persistent eosinophilia‘‘pneumonia’’/pulmonary infiltrates, or persistent eosinophilia most common presentation =>1.asthma 2. mononeuritis most common presentation =>1.asthma 2. mononeuritis 3 phases: prodromal phase (AR and asthma), eosinophilia and 3 phases: prodromal phase (AR and asthma), eosinophilia and

eosinophilic tissue infiltrates, vasculitic phase with visceral eosinophilic tissue infiltrates, vasculitic phase with visceral involvementinvolvement

Pulmonary imaging: subpleural ground-glass opacities, lobular Pulmonary imaging: subpleural ground-glass opacities, lobular consolidation,centrilobular nodules, bronchial wall thickening, consolidation,centrilobular nodules, bronchial wall thickening, mediastinal or hilar lymphadenopathy, and pleural or pericardial mediastinal or hilar lymphadenopathy, and pleural or pericardial effusioneffusion


Churg-Strauss syndromeChurg-Strauss syndrome

Different presentation forms in Churg-Strauss syndrome. (A) Chest X-ray of a 22-year-old man who presented with asthma, allergic Different presentation forms in Churg-Strauss syndrome. (A) Chest X-ray of a 22-year-old man who presented with asthma, allergic rhinitis, eosinophilia and recurrent pulmonary infiltrates for 2 years until he developed cutaneous lesions which led to diagnosis. (B) A 48-rhinitis, eosinophilia and recurrent pulmonary infiltrates for 2 years until he developed cutaneous lesions which led to diagnosis. (B) A 48-year-old man who had asthma and recurrent sinusitis for 12 years abruptly presented with abdominal angina, eosinophilia and severe year-old man who had asthma and recurrent sinusitis for 12 years abruptly presented with abdominal angina, eosinophilia and severe mononeuritis multiplex. Sural nerve biopsy revealed necrotizing vasculitis. The picture shows remaining right cubital and median palsy mononeuritis multiplex. Sural nerve biopsy revealed necrotizing vasculitis. The picture shows remaining right cubital and median palsy several months after diagnosis.several months after diagnosis.


Churg-Strauss syndromeChurg-Strauss syndrome

Peripheral eosinophilia (absolute eosinophil usually>1500)Peripheral eosinophilia (absolute eosinophil usually>1500) Increased ESR,CRP, and IgE levelIncreased ESR,CRP, and IgE level ANCA positive 50% of cases (predominantly MPO-pANCA)ANCA positive 50% of cases (predominantly MPO-pANCA) Histology: eosinophilic tissue infiltrates, extravascular Histology: eosinophilic tissue infiltrates, extravascular

‘‘allergic’’ granulomas, and small-vessel necrotizing vasculitis ‘‘allergic’’ granulomas, and small-vessel necrotizing vasculitis Association between LTAs and CSS remains unclearAssociation between LTAs and CSS remains unclear 62 pts. CSS take LTAs, 57 had CSS within first year 62 pts. CSS take LTAs, 57 had CSS within first year Prednisone (1 mkd) alone is effective Prednisone (1 mkd) alone is effective Life-threatening :glucocorticoids and oral CYC (2 mkd)Life-threatening :glucocorticoids and oral CYC (2 mkd) IVIG, MTX, IFN-a (uncontrolled studies) IVIG, MTX, IFN-a (uncontrolled studies) Cardiac involvement:main cause of death Cardiac involvement:main cause of death


Potential targets for biologicals interfering with lymphoid neoformation in WG-granulomata as key to self-perpetuating Potential targets for biologicals interfering with lymphoid neoformation in WG-granulomata as key to self-perpetuating inflammation, autoimmunity and ANCAinduced vasculitis in WG: After hypothetical barrier dysfunction and potential exogenous inflammation, autoimmunity and ANCAinduced vasculitis in WG: After hypothetical barrier dysfunction and potential exogenous triggers (e.g., triggers (e.g., S. aureus), PR3 is released from neutrophil granulocytes. PR3 induces DC S. aureus), PR3 is released from neutrophil granulocytes. PR3 induces DC maturation via the protease-activated maturation via the protease-activated receptor (PAR)-2. PR3 also enhances proinflammatory IL-32 action.39 Dendritic cells (DCs) and other antigen-presenting cells receptor (PAR)-2. PR3 also enhances proinflammatory IL-32 action.39 Dendritic cells (DCs) and other antigen-presenting cells (APCs) induce a Th1-type effector memory T-cell (TEM) response via cytokines such as IL-15 (?) and PR3-specific T cells. (APCs) induce a Th1-type effector memory T-cell (TEM) response via cytokines such as IL-15 (?) and PR3-specific T cells. Subsequent granuloma formation might provide the necessary “proinflammatory environment” for the break of tolerance. In this Subsequent granuloma formation might provide the necessary “proinflammatory environment” for the break of tolerance. In this environment the antiapoptotic capacity of IL-15 may counteract the mechanisms supporting self-tolerance. Lymphoid-like tissue environment the antiapoptotic capacity of IL-15 may counteract the mechanisms supporting self-tolerance. Lymphoid-like tissue neoformation in WG-granulomata could sustain autoimmunity to PR3. PR3-ANCA formation results in PR3-ANCA–associated neoformation in WG-granulomata could sustain autoimmunity to PR3. PR3-ANCA formation results in PR3-ANCA–associated vasculitis, giving rise to further inflammatory lesions. Genetic factors predispose to granulomatous inflammation (HLA-vasculitis, giving rise to further inflammatory lesions. Genetic factors predispose to granulomatous inflammation (HLA-DPB1 0401) and PR3-ANCA seropositivity (PTPN22 620W), thereby determining disease progression.40 Anti-TNF- treatment ∗ ∗DPB1 0401) and PR3-ANCA seropositivity (PTPN22 620W), thereby determining disease progression.40 Anti-TNF- treatment ∗ ∗may interfere with TNF--induced APC activation in granuloma formation, endothelial cell activation, and priming of neutrophils in may interfere with TNF--induced APC activation in granuloma formation, endothelial cell activation, and priming of neutrophils in vasculitis induction.B cell depletion by anti-CD20 antibodies could interfere with PR3-ANCA production andvasculitis induction.B cell depletion by anti-CD20 antibodies could interfere with PR3-ANCA production andother B cell functions (cytokine production, interaction with T cells, APC function).other B cell functions (cytokine production, interaction with T cells, APC function).

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESANNALS OF THE NEW YORK ACADEMY OF SCIENCES

Expert Opin. Investig. Drugs (2007) Expert Opin. Investig. Drugs (2007) 16(5)16(5)

Polyarteritis nodosaPolyarteritis nodosa

medium-vessel diseasemedium-vessel disease Incidence 2- 9 per million annuallyIncidence 2- 9 per million annually Men = womenMen = women constitutional symptoms, HT,musculoskeletal symptoms, constitutional symptoms, HT,musculoskeletal symptoms,

symptoms from vasculitic involvement of nerves, GI tract , skin, symptoms from vasculitic involvement of nerves, GI tract , skin, heart, and nonglomerular renal vessels heart, and nonglomerular renal vessels

suspected immunologic diseasesuspected immunologic disease Biopsy specimens : necrotizing inflammation involving medium-Biopsy specimens : necrotizing inflammation involving medium-

sized or small arteries,with abundant neutrophils, fibrinoid sized or small arteries,with abundant neutrophils, fibrinoid changes, disruption of the internal elastic laminachanges, disruption of the internal elastic lamina

Angiographic changes : microaneurysms ,stenoses, occlusion, Angiographic changes : microaneurysms ,stenoses, occlusion, beaded pattern beaded pattern


Polyarteritis nodosaPolyarteritis nodosa

severe life-threatening disease ( GI tract, heart, or CNS severe life-threatening disease ( GI tract, heart, or CNS system): 2 mkd oral CYC and glucocorticoidssystem): 2 mkd oral CYC and glucocorticoids

non–life or non–organ-threatening : glucocorticoids alone non–life or non–organ-threatening : glucocorticoids alone Plasma exchange in severe casesPlasma exchange in severe cases 5-year survival rate with treatment 80%5-year survival rate with treatment 80% Relapses are infrequent (8- 19%) Relapses are infrequent (8- 19%) PAN-like vasculitis ass. with viral inf. eg. HBV,HCV , HIVPAN-like vasculitis ass. with viral inf. eg. HBV,HCV , HIV Rx with glucocorticoids , antiviral treatment , and plasma Rx with glucocorticoids , antiviral treatment , and plasma

exchange induced remission 81% , relapse 10% exchange induced remission 81% , relapse 10% If clinical improvement , immunosuppression should be If clinical improvement , immunosuppression should be

withdrawn while continuing antiviral treatmentwithdrawn while continuing antiviral treatment


Clinics in Dermatology (2006) 24, 414– 429Clinics in Dermatology (2006) 24, 414– 429

Cutaneous vasculitisCutaneous vasculitis

most commonly vasculitic manifestation in clinical practicemost commonly vasculitic manifestation in clinical practice presumed drug allergy or chronic urticariapresumed drug allergy or chronic urticaria palpable purpura, necrotic papules, cutaneous infarcts, palpable purpura, necrotic papules, cutaneous infarcts,

urticaria, hemorrhagic vesicles, indurated erythema, or urticaria, hemorrhagic vesicles, indurated erythema, or ulcerative lesionsulcerative lesions

Histology: dermal small-vessel inflammation , often with Histology: dermal small-vessel inflammation , often with leukocytoclasisleukocytoclasis

idiopathic or occur because of medications, infections, idiopathic or occur because of medications, infections, allergies,malignancies, CNT dis., or primary vasculitisallergies,malignancies, CNT dis., or primary vasculitis

Diagnosis of exclusion Diagnosis of exclusion Rx: observation and measures such as leg elevation.Rx: observation and measures such as leg elevation.


Cutaneous vasculitisCutaneous vasculitis

Glucocorticoids (no optimal regimen)Glucocorticoids (no optimal regimen) Other medications : NSAIDs,Other medications : NSAIDs, dapsone, colchicine , dapsone, colchicine ,

antihistamines , and pentoxifyllineantihistamines , and pentoxifylline severe idiopathic cutaneous vasculitis : MTX or AZA severe idiopathic cutaneous vasculitis : MTX or AZA


Cryoglobulinemic vasculitisCryoglobulinemic vasculitis

Mixed cryoglobulinaemia may manifest with recurrent purpura and arthralgia only, as shown in(A), or may produce severe ischaemic Mixed cryoglobulinaemia may manifest with recurrent purpura and arthralgia only, as shown in(A), or may produce severe ischaemic lesions and organ dysfunction as displayed in (B) where necrotic toes and peroneal palsy can be clearly appreciatedlesions and organ dysfunction as displayed in (B) where necrotic toes and peroneal palsy can be clearly appreciated


Cryoglobulinemic vasculitisCryoglobulinemic vasculitis Cryoglobulins : mono or polyclonal Ig precipitate at temp. < Cryoglobulins : mono or polyclonal Ig precipitate at temp. <

37º C and redissolve on warming37º C and redissolve on warming lymphoid neoplasms, chronic infections, and inflammatory lymphoid neoplasms, chronic infections, and inflammatory

and autoimmune diseasesand autoimmune diseases Hepatitis C infection is leading cause of cryoglobulinemiaHepatitis C infection is leading cause of cryoglobulinemia Small vessel vasculitis caused by deposition of circulating Small vessel vasculitis caused by deposition of circulating

immune complexes (cryoglobulins and complement)immune complexes (cryoglobulins and complement) drug-induced or other allergy-related skin rashdrug-induced or other allergy-related skin rash clinical triad : recurrent palpable purpura (100%), clinical triad : recurrent palpable purpura (100%),

polyarthralgias (73%), and renal disease (55%)polyarthralgias (73%), and renal disease (55%) Pathology of glomeruli :deposition of IgG, IgM, and Pathology of glomeruli :deposition of IgG, IgM, and

complement, with coexistent renal arteritis complement, with coexistent renal arteritis


Cryoglobulinemic vasculitisCryoglobulinemic vasculitis

Patients with HCV–associated CV, antiviral Rx=> first linePatients with HCV–associated CV, antiviral Rx=> first line Severe case (eg. Vasculitis )=> glucocorticoids, CYC, or AZA Severe case (eg. Vasculitis )=> glucocorticoids, CYC, or AZA Plasma exchange serves to remove immune complexesPlasma exchange serves to remove immune complexes Rituximab used for resistant CV or setting of B-cell Rituximab used for resistant CV or setting of B-cell

lymphoproliferative disorderslymphoproliferative disorders Rituximab,with interferon and ribavirin : favorable results in Rituximab,with interferon and ribavirin : favorable results in

management of HCV–associated CVmanagement of HCV–associated CV..


Kawasaki diseaseKawasaki disease Acute vasculitis that affects childrenAcute vasculitis that affects children Primary cause of acquired heart disease in children from the Primary cause of acquired heart disease in children from the

united states and japanunited states and japan 80% of cases occur < 5 yrs. , Boys >1.5 times than girls80% of cases occur < 5 yrs. , Boys >1.5 times than girls Incidence in japan 112/100,000 among children <5 years oldIncidence in japan 112/100,000 among children <5 years old In US asian 32.5/100,000 , in white 9.1/100,000 In US asian 32.5/100,000 , in white 9.1/100,000 Fever at least 5 days, rash, conjunctival injection, and oral Fever at least 5 days, rash, conjunctival injection, and oral

mucosal changes. Extremity changes, including brawny mucosal changes. Extremity changes, including brawny induration, followed by desquamation; cervical adenopathyinduration, followed by desquamation; cervical adenopathy

Coronary artery abnormalities can be diagnosedCoronary artery abnormalities can be diagnosed Cardiac involvement is most of morbidity and mortalityCardiac involvement is most of morbidity and mortality


Kawasaki diseaseKawasaki disease

IVIG (2 g/kg) single infusion prevent coronary aneurysm IVIG (2 g/kg) single infusion prevent coronary aneurysm formation (appear 1-4wks after onset,15-25% of untreated ), formation (appear 1-4wks after onset,15-25% of untreated ), lessen fever, and reduce myocardial inflammationlessen fever, and reduce myocardial inflammation

Aspirin (80-100 mkd) concurrently with IVIG, but not affect Aspirin (80-100 mkd) concurrently with IVIG, but not affect coronary artery aneurysm formationcoronary artery aneurysm formation

refractory case : anecdotal experience with glucocorticoids, refractory case : anecdotal experience with glucocorticoids, pentoxifylline, plasma exchange, ulinastatin, abciximab (for pentoxifylline, plasma exchange, ulinastatin, abciximab (for large aneurysms), infliximab, and CYClarge aneurysms), infliximab, and CYC

Echocardiogram recommended at baseline and at 2, 6, and 8 Echocardiogram recommended at baseline and at 2, 6, and 8 weeks after onset of the diseaseweeks after onset of the disease

MRI/MRA, ultrafast CT, stress test, myocardial perfusion MRI/MRA, ultrafast CT, stress test, myocardial perfusion studies, and conventional angiographystudies, and conventional angiography


Kawasaki diseaseKawasaki disease

aneurysms resolve within 1-2 yrs. depend on size, age of onset aneurysms resolve within 1-2 yrs. depend on size, age of onset of disease, shape of the aneurysm (fusiform more likely than of disease, shape of the aneurysm (fusiform more likely than saccular), and location (distal more likely than proximal )saccular), and location (distal more likely than proximal )

Children with multiple aneurysms, giant aneurysms, or Children with multiple aneurysms, giant aneurysms, or coronary artery obstruction require close follow-up and coronary artery obstruction require close follow-up and possible long-term anticoagulationpossible long-term anticoagulation


Henoch-SchÖnlein purpuraHenoch-SchÖnlein purpura

small-vessel vasculitissmall-vessel vasculitis predominantly affects childrenpredominantly affects children suspected drug allergy or immunologic conditionsuspected drug allergy or immunologic condition Purpura (100%), arthritis (82%), abdominal pain (63%), GI Purpura (100%), arthritis (82%), abdominal pain (63%), GI

bleeding (33%), and nephritis (40%)bleeding (33%), and nephritis (40%) Uncommon : bullous skin lesions, testicular involvement , Uncommon : bullous skin lesions, testicular involvement ,

seizures, intestinal obstructionseizures, intestinal obstruction Complication : intussusception , ESRD ( 2- 5%)Complication : intussusception , ESRD ( 2- 5%) Recurrence occurs in up to 40% ( mostly first 3 months)Recurrence occurs in up to 40% ( mostly first 3 months) tissue Bx : leukocytoclastic vasculitis with IgA deposition tissue Bx : leukocytoclastic vasculitis with IgA deposition

in blood vessel wallsin blood vessel wallsJ ALLERGY CLIN IMMUNOL JUNE 2009J ALLERGY CLIN IMMUNOL JUNE 2009

Henoch-SchÖnlein purpuraHenoch-SchÖnlein purpura Typically self-limitedTypically self-limited Glucocorticoids might lessen tissue edema, arthritis, and Glucocorticoids might lessen tissue edema, arthritis, and

abdominal discomfort and decrease risk of intussusception , abdominal discomfort and decrease risk of intussusception , not prevent recurrence of abdominal symptoms, skin not prevent recurrence of abdominal symptoms, skin involvement, or renal disease and not shorten duration or involvement, or renal disease and not shorten duration or lessen relapselessen relapse

Active glomerulonephritis and progressive renal Active glomerulonephritis and progressive renal insufficiency : glucocorticoids combined cytotoxic agent insufficiency : glucocorticoids combined cytotoxic agent

Outcome usually excellent in children, in adults more severeOutcome usually excellent in children, in adults more severe Predictors of progression to ESRD: proteinuria (>1 g/d) , HT , Predictors of progression to ESRD: proteinuria (>1 g/d) , HT ,

renal impairment at presentation, age < 30 years, male sex , renal impairment at presentation, age < 30 years, male sex , crescents < 50% of glomeruli, and TI fibrosis on renal Bxcrescents < 50% of glomeruli, and TI fibrosis on renal Bx


Urticarial vasculitisUrticarial vasculitis Resembling urticaria Resembling urticaria Skin biopsy : inflammation of dermal capillaries and Skin biopsy : inflammation of dermal capillaries and

postcapillary venules postcapillary venules Chronic or subacute urticariaChronic or subacute urticaria Urticaria (usually >24 hours), violaceous color ,burning pain Urticaria (usually >24 hours), violaceous color ,burning pain

more frequent than pruritus, and residual pigmentation after more frequent than pruritus, and residual pigmentation after resolution resolution

Involve GI, musculoskeletal ,renal , and pulmonary (particularly Involve GI, musculoskeletal ,renal , and pulmonary (particularly COPD) , less commonly in ocular and central nervous systemsCOPD) , less commonly in ocular and central nervous systems

Confirmed by skin biopsy ( LCV, Ig, complement, fibrin Confirmed by skin biopsy ( LCV, Ig, complement, fibrin deposition at dermalepidermal junction and around blood deposition at dermalepidermal junction and around blood vesselsvessels


Urticarial vasculitisUrticarial vasculitis

classified as normo- or hypocomplementemic UVclassified as normo- or hypocomplementemic UV normocomplementemic UVare idiopathic(most), remainder ass. normocomplementemic UVare idiopathic(most), remainder ass.

With monoclonal gammopathy, neoplasia, UV light sensitivity, With monoclonal gammopathy, neoplasia, UV light sensitivity, or repeated cold exposure.or repeated cold exposure.

Hypocomplementemic UV due to SLE,SjÖgren syndrome, Hypocomplementemic UV due to SLE,SjÖgren syndrome, serum sickness reaction, or neoplasia or HUVSserum sickness reaction, or neoplasia or HUVS

HUVS : specific autoimmune disorder involves >6 mo. of UV HUVS : specific autoimmune disorder involves >6 mo. of UV with hypocomplementenia in presence of angioedema , with hypocomplementenia in presence of angioedema , moderate-to-severe COPD(occurs in 50%), ocular inflammation moderate-to-severe COPD(occurs in 50%), ocular inflammation (uveitis occurs in 30%), and glomerulonephritis.(uveitis occurs in 30%), and glomerulonephritis.

C3, C4, C1q levels are low , anti-C1q antibody levels (C1q C3, C4, C1q levels are low , anti-C1q antibody levels (C1q precipitins) are detectable precipitins) are detectable


Urticarial vasculitisUrticarial vasculitis

Treatment based on the severity and underlying diseaseTreatment based on the severity and underlying disease skin : antihistamines+/- short course of glucocorticoids , skin : antihistamines+/- short course of glucocorticoids ,

colchicine, dapsone, hydroxychloroquine, pentoxifylline,and colchicine, dapsone, hydroxychloroquine, pentoxifylline,and indomethacinindomethacin

montelukast, cyclosporine A, and AZA used in combinations montelukast, cyclosporine A, and AZA used in combinations as sequential treatment if patients had suboptimal response to as sequential treatment if patients had suboptimal response to treatment with cinnarizine and glucocorticoids for 6 monthstreatment with cinnarizine and glucocorticoids for 6 months

HUVS or systemic disease : require initial glucocorticoid HUVS or systemic disease : require initial glucocorticoid therapy therapy


Semin Arthritis Rheum 38:348-360Semin Arthritis Rheum 38:348-360

Presentations of vasculitic syndromes to the allergist/immunologist

Vasculitic syndrome Presentation to allergist/immunologist

GCA ‘‘Sinus’’ headache

TAK Headache

WG Recurrent sinusitis, nosebleed and nasal crusting, otitis media, cough, hoarseness, nonresolving ‘‘pneumonia’’/pulmonary infiltrates

MPA cough +/- hemoptysis, nonresolving ‘‘pneumonia’’/pulmonary infiltrates

CSS Allergic rhinitis, nasal polyposis, asthma, nonresolving ‘‘pneumonia’’/pulmonary infiltrates, eosinophilia

PAN Suspected immunologic disease, postprandial abdominal pain with suspected food allergy

KD Skin rash, soft tissue edema

Cutaneous

vasculitis

Skin lesions in which an allergy or drug reaction might be suspected

CV Skin lesions in which an allergy or drug reaction might be suspected

HSP Purpura, soft tissue edema, or both in which an allergy might be suspected; food enterocolitis

UV Chronic or subacute urticaria, angioedema


Update on vasculitis

Health & Medicine

Transcript of Update on vasculitis