Vasculitides Mohamed Fouad MD. Internal Medicine Nephrology Unit . Zagazig University

Definition

Vasculitides Blood vessel inflammation Histological triad Leukocyte infiltration Fibrinoid necrosis of the blood vessel wall Thrombotic vascular occlusion. Only part of large-vessels wall is affected Inflammation lead to weakness and aneurysm formation Most serious consequences Infarction of vital organs Haemorrhage resulting from ruptured aneurysms.

Classification

} } Chapel Hill Classification ANCA immune Pauci Immune Complex Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis Aorta Major tributaries Medium vessel vasculitis Classical polyarteritis nodosa Kawasaki’s disease Medium and small sized Arteries and arterioles. Necrotising arteritis Inflammatory aneurysms ANCA } Small vessel vasculitis immune Microscopic polyangiitis Wegener’s granulomatosis Churg–Strauss syndrome Pauci Small intraparenchymal Arteries Arterioles Capillaries Venules } Henoch–Schِnlein purpura Hypersensitivity vasculitis Essential cryoglobulinaemia Immune Complex

Chapel Hill Classification Variable vessel vasculitis (VVV) Behc¸et’s disease (BD) Cogan’s syndrome (CS) Single organ vasculitis (SOV) Cutaneous leukocytoclastic angiitis Cutaneous arteritis Primary CNS vasculitis Isolated aortitis, others Vasculitis associated with systemic disease Lupus vasculitis Rheumatoid vasculitis Sarcoid vasculitis, others

Chapel Hill Classification Vasculitis associated with probable etiology Hepatitis C virus-associated cryoglobulinemic vasculitis Hepatitis B virus-associated vasculitis Syphilis-associated aortitis Drug-associated immune complex vasculitis Drug-associated ANCA-associated vasculitis Cancer-associated vasculitis, others

Chapel Hill Classification

Pathogenesis

Mechanisms of Vessel Damage Pathogenic immune complex formation and or deposition Henoch-Schönlein purpura   Vasculitis associated with collagen vascular diseases   Serum sickness and cutaneous vasculitis syndromes   Hepatitis C–associated essential mixed cryoglobulinemia   Hepatitis B–associated polyarteritis nodosa Production of antineutrophilic cytoplasmic antibodies  Wegener's granulomatosis.90%PR3-ANCA ,20% MPO-ANCA  Microscopic polyangiitis .40%PR3-ANCA ,60% MPO-ANCA Renal limited vasculitis Nephritis 10–30%PR3 , 30–70%MPO Churg-Strauss syndrom………….10% PR3 ,30–70%MPO Pathogenic T lymphocyte responses and granuloma formation   Giant cell arteritis   Takayasu's arteritis   Wegener's granulomatosis   Churg-Strauss syndrome

Role of ANCAs Proteinase 3 (PR3) PR3-ANCA ANCAs are directed against antigens that reside within the primary granules of neutrophils and monocytes. Two types of ANCA are relevant to vasculitis: Proteinase 3 (PR3) PR3-ANCA Myeloperoxidase (MPO) MPO-ANCA. PR3-ANCA Striking and unexplained feature of ANCA- associated vasculitis is that patients virtually never have antibodies to both PR3 and MPO Staining on ethanol ANCA titres are generally measured using ELISA and indirect immunofluorescence MPO-ANCA

Role of ANCAs Viral infection Priming of neutrophils Adherence TNF IL-1 IL-8 in situ LeuB4 Express Viral infection Priming of neutrophils Adherence vasculitis Pr3 or MPO

Role of ANCAs Patients with PR-3 ANCA are more than one and a half times as likely to relapse when compared to those with MPO -ANCA ANCA may sometimes be positive with other inflammatory conditions *Inflammatory bowel disease *Rheumatoid disease *Bacterial endocarditis *Cystic fibrosis. *Chronic inflammatory liver disease In this setting, specificity of the ANCA may not be against PR3 or MPO but against other neutrophil antigens, including lactoferrin, cathepsin G, and anti–bactericidal/permeability- increasing protein.

LAMP-2 Recently, autoantibodies to lysosomal membrane protein 2 (LAMP-2) were reportedly identified in the circulation of most patients with either MPO-ANCA or PR3-ANCA. LAMP-2 has homology to the bacterial adhesin FimH, and thus autoantibodies to LAMP-2 may arise by molecular mimicry secondary to infection. Rats injected with anti–LAMP-2 or immunized with FimH develop pauci-immune focal necrotizing and crescentic GN. If these exciting observations are confirmed, anti–LAMP-2 antibodies will be a useful marker for pauci-immune small- vessel vasculitis but also may prove to be critically important in the pathogenesis of pauci-immune vasculitis and GN.

Complement in ANCA vasculitis It was previously assumed that the complement system is not involved in the development of ANCA-associated vasculitis due to its ‘‘pauci-immune’’ feature in renal histology. Increasing evidence indicates that activation of the complement system, especially via the alternative complement pathway Among various components of the complement system, the interaction between C5a and its receptors plays a central role in the pathogenesis of AAV. Inhibition of complement, especially C5a, is a potential therapeutic approach to AAV.

Clinical Presentation

Clinical Presentation Strongly suggestive signs Mononeuritis multiplex Palpable purpura Pulmonary-renal involvement Exclude Sepsis Drug toxicity Malignancy Coagulopathy

Clinical Presentation Constitutional Fever, weight loss, malaise Peripheral nerve Mononeuritis multiplex peripheral neuropathy Joint & muscle: Arthralgia Arthritis Myalgia Gastrointestinal: Abdominal angina Nausea, vomiting Bowel infarction Bleeding Perforation Cholecystitis Hepatic infarction Pancreatic infarction

Clinical Presentation Skin Palpable purpura Cutaneous infarcts Digital infarction Livedo reticularis Raynaud’s ph.

Clinical Presentation Heart: Congestive heart failure Myocardial infarction Pericarditis CNS: Cerebral vascular accident Seizure Altered mental status Eye: Retinal hemorrhage Retinal vasculitis Genitourinary: Testicular pain Ovarian pain Epididymal pain

Clinical Presentation Renal presentation of systemic vasculitis Hematuria Proteinuria Hypertension Rapidly progressive glomerulonephritis

Specific vasculitic diseases

Giant Cell Arteritis

Giant Cell Arteritis Other name Definition: Epidemiology Cranial arteritis Definition: Granulomatous arteritis of the aorta and its major branches Predilection for the extracranial branches of the carotid artery Often involves the temporal artery Often is associated with PMR. Epidemiology Almost all in > 50 yrs Almost all in whites F/M ratio = 2/1 Sibling: x 10 Incidence: 7-33/100,000 in > 50 yrs

ACR Diagnostic Criteria Age ≥ 50 years at time of disease onset Localized headache of new onset Tenderness or decreased pulse of the temporal artery ESR greater than 50 mm/h Biopsy that includes an artery, reveals a necrotizing arteritis predominance of mononuclear cells or a granulomatous process with multinucleated giant cells At least 3 criteria must be present for diagnosis Sensitivity 93.5%, specificity 91.2% Scalp necrosis

Takayasu's arteritis

Takayasu's arteritis Other names: Epidemiology Definition: Aortic arch syndrome Pulseless disease Definition: Granulomatous inflammation of the aorta & its major branches Multisystem involvement Predilection for aortic arch & its branches Pulseless extremities Epidemiology Incidence: 1.2-2.6/1000,000 F/M ratio : 8/1 Age: 10-30 yrs (< 50) More common in the orient

ACR Diagnostic Criteria Age at disease onset ≤40 years Claudication of the extremities Decreased pulsation of one or both brachial arteries Difference of at least 10 mmHg in SBP between the arms Bruit over one or both subclavian A. or the abdominal aorta Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large arteries in proximal upper or lower limb At least 3 criteria must be present for diagnosis Sensitivity 90.5%, specificity 97.8%

Polyarteritis nodosa (PAN).

Polyarteritis nodosa (PAN). Other names: Periarteritis nodosa Panarteritis nodosa Definition: Necrotizing inflammation without glomerulonephritis Multisystem disease Medium & small vessel V Renal & visceral involvement Epidemiology Uncommon M/F ratio : 1.6 – 2 / 1 All race Mid-40s to mid60s Mean age : 48 yrs

ACR Diagnostic Criteria Unexplained weight loss > 4 kg Livedo reticularis Testicular pain or tenderness Myalgias , weakness, or polyneuropathy Mononeuropathy or polyneuropathy New onset diastolic blood pressure > 90 mmHg Elevated levels of serum BUN >40 mg/dL or Cr >1.5 mg/dL

ACR Diagnostic Criteria Evidence of hepatitis B virus infection via antibody or antigen Characteristic arteriographic abnormalities A biopsy of small- or medium-sized artery containing polymorphonuclear cells At least 3 of 10 criteria must be present for diagnosis These criteria have a reported sensitivity of 82.2% and a reported specificity of 86.6%

Polyarteritis nodosa (PAN). Dermal and SC nodules on the pretibial aspects of the lower leg Starburst pattern seen in the supra- and retromalleolar region These lesions represent cutaneous infarction with ulceration Nodules on sole of foot in cutaneous polyarteritis nodosa Necrotic lesions of PAN

Kawasaki's disease

Kawasaki's disease Definition: Epidemiology KD is a vasculitis of unknown etiology Multisystem involvement Small to medium-sized arteries with resulting Aneurysm formation. Epidemiology The disease affects boys more than girls Affect children of all races, more common among of Asian. Seasonal variability The incidence :6 / 100,000 in children> 5 yrs.

ACR Diagnostic Criteria Bilateral non exudative conjunctivitis Oral mucous membrane changes, including injected or fissured lips, injected pharynx, or strawberry tongue Erythema, edema of palms or soles, periungual desquamation Erythematous truncal rash Cervical lymphadenopathy (at least one lymph node >1.5 cm) Besides fever, four of the other criteria must be positive for diagnosis

Granulomatosis with polyangiitis

Granulomatosis with polyangiitis (GPA) Other name Wegener's disease Definition: Granulomatous inflammation Necrotizing vasculitis affecting small to medium sized vessels Necrotizing glomerulonephritis is common Multisystem disease involving upper & lower respiratory tracts Epidemiology Uncommon disease 1 in 20,000 to 1 in 30,000 people Occur at any age Appears to affect men and women in equal proportions 97% percent of patients were white

ACR Diagnostic Criteria Nasal or oral inflammation (painful or painless oral ulcers or purulent or bloody nasal discharge). Abnormal CXR showing nodules, fixed infiltrates, or cavities. Abnormal urinary sediment (microscopic hematuria or RBC casts). Granulomatous inflammation on biopsy of an artery or perivascular area. Almost all patients with active systemic Wegener granulomatosis have a positive proteinase 3 ANCA At least 2 of these four criteria must be present for diagnosis Sensitivity 88%, specificity 92%

Wegener's disease Saddle-nose deformity Large ulcer on the palate covered by a dense, adherent, necrotic mass; accompanying edema of the upper lip. Thick-walled right upper lobe cavity in Wegener granulomatosis.

Microscopic polyangiitis

Microscopic polyangiitis Definition: Systemic necrotizing vasculitis Small vessel: capillary, venule, arteriol Multisystem involvement: Glomerulonephritis Pulmonary capillaritis Others Epidemiology: Mean age: 57 yrs M/F ratio > 1

Microscopic polyangiitis Microscopic polyangiitis (MPA) is vasculitis of small vessels. It was initially considered as a microscopic form of PAN American College of Rheumatology developed classification criteria for several types of systemic vasculitis but did not distinguish between polyarteritis nodosa and microscopic polyarteritis nodosa. MPA and Wegener granulomatosis seem to be part of a clinical spectrum. However Absence of granuloma formation and Sparing of the upper respiratory tract are features of MPA.

Churg-Strauss syndrome

Eosinophilic granulomatosis with polyangiitis (EGPA) Other name: Churg-Strauss syndrome Allergic angiitis & granulomatosis Definition: Small- to medium-sized Multisystem involvement Eosinophilia Extravascular granuloma Associated with asthma Epidemiology: Incidence: 1-3/1000,000 Mean age: 48 yrs F/M ratio: 1.2/1

ACR Diagnostic Criteria Asthma (a history of wheezing ) Eosinophilia of >10 percent on differential WBC count Mononeuropathy (including multiplex) or polyneuropathy Migratory or transient pulmonary opacities , radiographically Paranasal sinus abnormality Biopsy containing a blood vessel showing eosinophils in extravascular areas. At least 4 of these six criterial must be present for diagnosis Specificity 99%, sensitivity 85%

Schoenlein-Henoch's purpura

Schoenlein-Henoch's purpura Other name: Anaphylactoid purpura Definition: Vasculitis with IgA-dominant immune deposits Affecting small vessels,capillaries, venules, or arterioles): Palpable purpura Arthritis GI involvement Glomerulonephritis Epidemiology: Children: 4-7 yrs M/F ratio: 1.5/1

ACR Diagnostic Criteria Palpable purpura Bowel angina Gastrointestinal bleeding Hematuria Age at onset ≤20 years lesion No new medications At least three or more criteria must be present for diagnosis Sensitivity 87.1%, specificity 87.7%

Hypersensitivity vasculitis

Hypersensitivity vasculitis Other names: Hypersensitivity vasculitis Leukocytoclastic vasculitis Definition: Small vessel vasculitis Isolated Skin involvement Without systemic vasculitis or glomerulonephritis. Epidemiology: Most common vasculitis Secondary: 70% Drugs, infection, CTD, neoplasm Idiopathic: 30%

Hypersensitivity vasculitis Age >16 Possible offending drug in temporal to the symptoms Palpable purpura Maculopapular rash Biopsy of a skin lesion showing neutrophils around an arteriole or venule The presence of three or more of these criteria sensitivity and specificity of 71 and 84 percent, respectively.

Essential cryoglobulinemic vasculitis 

Essential cryoglobulinemic vasculitis Definition: Cryoglobulin immune deposits Affecting small vessels (ie, capillaries, venules, or arterioles) Associated with cryoglobulins in serum Skin and glomeruli are often involved Cryoglobulins Immunoglobulins that precipitate out up on exposure to cold temperatures. Three types, depending on whether the cryoprecipitate is monoclonal, polyclonal or a combination

Cryoglobulins Type 1: Monoclonal IgM cryoglobulin: Waldenström’s macroglobulinaemia; C/P of hyperviscosity Type 2: Mixed monoclonal/polyclonal cryoglobulin: Seen in chronic infections, eg hepatitis C Rheumatoid factor Type 3: Polyclonal cryoglobulin: Seen in connective tissue diseases, eg Sjögren / SLE

ACR Diagnostic Criteria Specific criteria for a diagnosis of essential cryoglobulinemic vasculitis have not yet been formulated. The diagnosis is typically made from History. Skin purpura. Low complement levels. Demonstration of circulating cryoglobulins. Histology showing small vessel inflammation with immune deposits found in the vascular walls. Acral ulcerations and necrosis may occur where peripheral temperature is less than core temperature

Differential diagnosis

Treatment

Giant cell arteritis Prednisone 60 mg/d ↓to 50 40 ↓10% 4 w. Rapid 2 w. ↓Every Prednisone 60 mg/d ↓to 50 40 ↓10% improve 1 - 2 w. Acute visual loss 1 g/d methylprednisolone for 3 to 5 days

Takayasu arteritis Prednisone 1 mg/kg 1-3 M Cytotoxic therapy CYC Relieve 25% to 100% Prednisone 1 mg/kg 1-3 M Persistent disease Cytotoxic therapy MTX 15 to 25 mg/wk + Prednisone ↑Remission and ↓ side effect CYC Severe disease . Unresponsive . Intolerant Surgery Stents Angioplasty By pass

Kawasaki’s disease + Intravenous immunoglobulin 2 g/kg Intravenous immunoglobulin Prevent coronary aneurysm ↓ myocardial inflammation Lessen fever + Aspirin 80 -100 mg/kg Multiple aneurysms Giant aneurysms Coronary obstruction Long-term anticoagulation Corticosteroid contraindicated

Polyarteritis nodosa + High-dose corticosteroids Beneficial 6 m-12 m. Beneficial + Cyclophosphamide 2 mg/kg Improves Antiviral agents Hepatitis B virus-associated PAN outcomes.

Wegener’s granulomatosis Fulminant Disease Threatening Life Methylprednisolone 1 g/d Prednisone.1mg/kg/day 3 days CYC 3-4 mg/kg/day ↓2 mg/kg per day 7 sets within 14 days Plasmapheresis benefit in patients with RPGN Replaced by 5% albumin 60 mg/kg. Patients with active severe WG 375 mg/m2 IV weekly Rituximab “anti-CD20” 4 weeks Before the development of treatment, mean survival time 5 months With treatment 5-year survival rate was 74%

Wegener’s granulomatosis Active WG Stopped 3-6m. Cyclophosphamide 2 mg/kg 4 weeks + improvement Tapered Prednisone 1 mg/kg per day Prednisone is tape 6-12 m. Remission Maintenance Discontinued MTX. 20 to 25 mg/wk AZA.2 mg/kg/day Mycophenolate mofetil Or Or

Wegener’s granulomatosis Active but Non Severe Disease Prednisone Effective And + inducing Maintaining remission For 2 y. MTX.20-25 mg/wk

European Vasculitis Study Group (MEPEX) Evaluated the efficacy of IV methylprednisolone as induction therapy or plasma exchange in patients who had a serum creatinine of more than 500 µmol/l. Plasma exchange compared with pulse methylprednisolone in this population increases the rate of recovery from renal failure and reduced risk of progression to ESRD , from 43% to 19% at 1 year Patient survival and adverse events were similar in patients who did or did not receive plasma exchange.

Henoch-Schönlein purpura Typically self-limited condition often does not require treatment Tissue edema Arthritis Abdominal discomfort ↓rate of intussusception Improve Glucocorticoids. Glucocorticoids + Cytotoxic agent Beneficial Active glomerulonephritis progressive renal insufficiency

Cryoglobulinemic vasculitis IFN-a + Ribavirin HCV-associated Cryoglobulinemic vasculiti ↑viremia Immunosuppressive drugs Transiently improve not practical Plasmapheresis Brief responses Rituximab Favorable results

Churg–Strauss syndrome CSS Asthma often persists Prednisone. 1 mg/kg / day Effective ↓Steroid discontinuation Glucocorticoids + CYC.2 mg/kg / day Life-threatening disease

Cutaneous vasculitis Glucocorticoids Non steroidal anti-inflammatory agents Antihistamines Dapsone Hydroxychloroquine. Colchicine Severe disease that is unresponsive to other measures Cytotoxic agents

Novel Therapies Plasmapheresis Intravenous Immunoglobulin Methotrexate Adjunctive therapy in patients with pulmonary hemorrhage or advanced renal disease Intravenous Immunoglobulin Adjunctive therapy in patients with persistent disease on standard therapy Methotrexate Alternative to cyclophosphamide in patients with “early disease” and without signifcant renal or pulmonary disease. Prevention of relapse?

Novel Therapies Mycophenolate mofetil Lefunomide Rituximab Infiximab Prevention of relapse? Lefunomide Prevention of relapse? Rituximab Adjunctive therapy for cyclophosphamide-resistant or relapsing patients? Induction therapy Infiximab Adjunctive therapy for cyclophosphamide-resistant or relapsing patients?

Novel Therapies Alemtuzumab Etanercept Adjunctive therapy for cyclophosphamide-resistant or relapsing patients? Etanercept Shown NOT to be efficacious in the prevention of relapse Trimethoprim/sulfamethoxazole Prevention of relapses that affect the upper respiratory tract

Thank you