Systemic vasculitis

Dr.

Overview ► Introduction ► Classification ► Pathogenesis ► Clinical features ► Differential diagnosis ► Management ► Conclusions

Introduction ► Systemic vasculitides are    Complex Often serious group of disorders which, While uncommon, require careful management in order to ensure optimal outcome ► Primary systemic vasculitis has an incidence of  > 100 new cases per million Clinical and Experimental Immunology 2010;160: 143–60

Introduction End Stage Renal Disease (ESRD)

Introduction ► Despite a significant reduction in mortality as a result of  Standard immunosuppression, most patients experience ► Poor quality of life, characterized by  Relapse, persisting low grade disease activity and increasing burden of drug toxicity Clinical and Experimental Immunology 2010;160: 143–60

Vasculitis classification– the first step

Primary Systemic Vasculitis classification

Classification of systemic vasculitis

Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis ►

Small vessel vasculitis

 Wegener’s granulomatosis  Churg-Strauss syndrome   Microscopic polyangiitis Henoch-Schonlein purpura ► ►   Essential cryoglobulinemic vasculitis Cutaneous leukocytoclastic angiitis  

Large-vessel vasculitis

  Polyarteritis nodosa Kawasaki disease Giant cell (temporal) arteritis Takayasu arteritis

Classification of systemic vasculitis ► 2 major groups based on clinical and histopathological features of vasculitis 1. Large vessel vasculitis: aorta and major branches ► ► Giant cell arteritis / temporal arteritis Takayasu arteritis 2. Medium-sized vasculitis: medium arteries ► Polyarteritis nodosa (PAN) ► Kawasaki disease

Classification of systemic vasculitis 2. medium-sized vasculitis: arterioles, capillaries and venules    Wegener’s granulomatosis (WG) Churg-Strauss syndrome (CSS) Microscopic polyangiitis (MPA) 3. small vessel vasculitis: venules, capillaries   Henoch Schonlein purpura (HSP) Cryoglobulinaemic vasculitis

Epidemiology Clinical and Experimental Immunology 2010;160: 143–60

Epidemiology ► Begin during the 5 th , 6 th , 7 th ► Male predominance decades of life ► Caucasians have greater incidence than African Americans ► Suspicion that Wegener’s more frequent in colder compared to warmer climates, and that microscopic polyangiitis has opposite trend

Pathogenesis of vasculitis J Allergy Clin Immunol 2009;123:1226-36

Pathogenesis of vasculitis ► Antibody mediated inflammation    Wegener’s granulomatosis (WG) Churg-Strass syndrome (CSS) Microscopic polyangiitis (MPA)

Pathogenesis of vasculitis ► Immune complex-mediated inflammation    Henoch Sch Ö lein purpura (HSP) Cryoglobulinaemic vasculitis Polyarteritis nodosa (PAN) ► Cell-mediated inflammation     Giant cell arteritis Takayasu arteritis Wegener’s granulomatosis (WG) Churg-Strass syndrome (CSS)

Pathogenesis ► ► All three associated with the presence in serum of autoantibodies against components of the cytoplasm of neutrophils: ANCA ANCA activates neutrophils, which then adhere to endothelial cells and release mediators of inflammation and cell injury

Clinical features J Allergy Clin Immunol 2009;123:1226-36

Definition – large vessel vasculitis Clinical and Experimental Immunology 2010;160: 143–60

Definition – medium vessel vasculitis Clinical and Experimental Immunology 2010;160: 143–60

Definition – small vessel vasculitis Clinical and Experimental Immunology 2010;160: 143–60

Small vessel pauci-immune vasculitis ►

Wegener’s granulomatosis

:  Necrotizing granulomatous inflammation, most often affecting respiratory tract ►

Churg-Strauss syndrome

:  Occurs in association with asthma, eosinophilia, and necrotizing granulomatous inflammation ►

Microscopic polyangiitis

:  Pauci-immune systemic vasculitis occurring in the absence of asthma and eosinophilia with no evidence of granulomatous inflammation

Clinical Manifestations

General symptoms ► Fever ► Malaise ► Anorexia ► Weight loss ► Myalgias ► Arthralgias

*less frequent in Churg-Strauss *hematuria, proteinuria and renal failure *renal failure usually has characteristics of rapidly progressive glomerulonephriti s Renal involvement

*Purpura most common in lower extremities, occurs as recurrent crops.

*Nodular lesions occur more frequently in Churg-Strauss and Wegener’s Skin

Upper and lower respiratory tract *pulmonary hemorrhage *nodular or cavitary lesions in Wegener’s and Churg-Strauss *subglottic stenosis, sinusitis, rhinitis, otitis media, ocular inflammation most common in Wegener’s

*identified in 50% of pts with Churg-Strauss *<20% in Wegener’s and microscopic polyangiitis *transient heart block, ventricular hypokinesis, infarction, myocarditis, endocarditis, pericarditis Cardiac

*typically abdominal pain, blood in the stool, mesenteric ischemia and rarely perforation *can also mimic pancreatitis and hepatitis Gastrointestinal

Diagnosis

Update on vasculitis: J Allergy Clin Immunol 2009

Update on vasculitis: J Allergy Clin Immunol 2009

Differential Dx of Vasculitis ► ► ► ► ► ► ► ► ► Fibromuscular dysplasia Cholesterol emboli Atrial myxoma with emboli

Infective endocarditis

Malignancies,ie lymphamatoid granulomatosis Bacteremia Rickettsial dz Amyloid SLE

Differential Diagnosis: Pulmonary-Renal Syndrome ► Goodpasture’s disease ► SLE ► Henoch-Schoenlein purpura ► Behcet’s syndrome ► Essential mixed cryoglobulinemia ► Rheumatoid vasculitis ► Drugs: penicillamine, hydralazine, propylthiouracil ► Acute renal failure with hypervolemia ► Severe cardiac failure ► Severe bacterial pna with renal failure ► Hantavirus infection ► Opportunistic infections ► ARDS w/ renal failure in multi-organ failure ► Paraquat poisoning ► Renal vein/IVC

Differential of Pulmonary Renal Syndrome Goodpasture’s Disease Systemic Vasculitis Wegener’s Granulomatosis

Microscopic Polyangiitis

Churg-Strauss Syndrome Cryoglobulinemia Henoch-Schonlein Purpura Connective Tissue Disease Polymyositis/Dermatomyositis Progressive Systemic Sclerosis SLE Primary Glomerular Disease IgA Nephropathy Post-Infectious GN Membranoproliferative GN

Anti-neutrophil cytoplasmic autoantibodies ► Serologic testing for ANCA is useful diagnostic test, but should be interpreted in the context of other patient characteristics ► Testing should include both indirect immunoflourescence microscopy (IFA) and enzyme immunoassay (EIA) ► Sensitivity for pauci-immune small vessel vasculitis and GN is 80-90% ► ¼- 1/3 of patients with anti-GBM crescentic GN and ¼ of patients with idiopathic immune-complex crescentic GN are ANCA positive  Pts with concurrent ANCA and anti-GBM antibodies have worse prognosis than those with ANCA alone

Anti-neutrophil cytoplasmic autoantibodies

Proteinase 3 (PR3/c-Anca)

70%

Myeloperoxidas e (MPO/p-ANCA)

25%

Negative

5% Wegener’s granulomatosis Microscopic polyangiitis Churg-Strauss syndrome Pauci-immune glomerulonephritis 40% 10% 20% 50% 60% 70% 10% 30% 10%

Pathologic diagnosis ► Biopsy of involved site      Skin Muscle Nerve Gut Kidney

Size of vessel involvement

► Glomerular vasculitis   Focal necrosis, crescents Rapidly progressive glomerulonephritis ► Extra-glomerular vasculitis  Arteritis of small/medium/large renal arteries

Polyarteritis nodosa Takayasu’ s arteritis

Crescentic glomerulonephritis Classification by immune deposits

Rapidly Progressive glomerulonephritis (RPGN) ► Definition and disease associations ►  

The kidney in ANCA vasculitis Pathogenesis

Treatment and outcomes

Renal vasculitis (glomerulonephritis): presentation ► Rapidly progressive glomerulonephritis  rising creatinine + crescents on biopsy (oliguria) ► Urine  haematuria, red cell casts + proteinuria ► Imaging  kidneys normal size

ANCA associated vasculitis

ANCA testing

ANCA induces neutrophil superoxide production

MPO-ANCA in Rag-/- mice Xiao et al, JCI, 2002

Epidemiology - ANCA associated vasculitis EUVAS; Lane 2004, Arthritis Rheum

Ultra violet light and incidence of vasculitis Gatenby, Arthritis Rheum 2009

Rapidly Progressive glomerulonephritis (RPGN) ► Definition and disease associations ►   The kidney in ANCA vasculitis Pathogenesis

Treatment and outcomes

EUVAS disease categorization of ANCA-associated vasculitis Therapeutics and Clinical Risk Management 2010:6 253 –264

Long-term follow up of ANCA vasculitis Flossmann, ASN 2007

Causes of death

ANCA-associated vasculitis: severity subgrouping Rasmussen et al., Glin Exp Immunol, 1995

Treatment

Induction therapy ► Corticosteroids and cyclophosphamide  Induces remission in ► ► 75% of patients at 3 mos and 90% at 6 mos

Maintenance therapy ► Intensity should be reduced as much as possible to reduce toxic side effects    Can stop induction therapy after 6-12 months if patient is in full remission and at low risk for relapse IV cyclophosphamide regimens afford 1/3-1/2 the total dose of cyclophosphamide given in oral regimens Can replace cyclophosphamide with azathioprine 2 mg/kg/day after 3-6 months ► Other therapies being studied include anti-TNF mycophenolate mofetil α (infliximab, etanercept), anti-CD20 (rituximab),

Relapse therapy ► One fourth to one half of patients will experience a relapse within several years  Diagnosis based on solid clinical and pathologic evidence of recurrent disease, not an increase in ANCA titers alone ► Most often, a treatment similar to induction regimen is used though less intensive or less toxic therapy may be adequate.

Renal transplantation ► Frequency of recurrence about 20%   Graft loss caused by recurrence < 5% Positive ANCA titer at time of transplant does not increase risk of recurrent disease in transplant ► Recurrent ANCA GN in transplant responds to therapy similarly to recurrent disease in native kidneys

Prognosis ► ► ► ► ► With adequate immunosuppressive therapy, 5-year renal and patient survival is 65-75% Older age, higher serum creatinine at presentation, pulmonary hemorrhage, and dialysis-dependent renal failure correlate with overall poor outcome Patients with MPO-ANCA have slightly better renal outcome Patients with PR3-ANCA have more extrarenal organ manifestations, higher chance for relapse and higher mortality Regardless of ANCA type, best clinical predictor of renal outcome is GFR at time of diagnosis. Best pathologic predictor of response to treatment is extent of active necrosis and cellular crescents in biopsy specimens

Remission induction:

cyclophosphamide + steroids 3 vs 12 months

Jayne, NEJM 2003

Treatment response in ‘generalised’ vasculitis Jayne, NEJM 2003

“CYCLOPS” IV cyclophosphamide regimen

Severe renal disease: additional therapy ► ► ►    IV methyl predsnisolone (1000-3000 mg) ? Plasma exchange Role of plasma exchange is controversial Klemmer et al: Retrospective review of all pts presenting to UNC 1995 2001 with DAH and small-vessel vasculitis. All treated w/ apheresis and IV cyclophosphamide and/or IV methylprednisolone. DAH resolved in 20/20 pts (100%) with average 6.4 treatments Pusey et al: Dialysis dependent patients (N=19) were more likely to have recovered renal function if tx with plasma exchange as well as drugs (10/11) compared to drugs alone (3/8). No difference in outcome in patients not on dialysis de Lind van Wijngaarden et al: 69 dialysis-dependent patients with ANCA associated glomerulonephritis received standard immunosuppressive therapy plus either IV methylpred or plasma exchange. Plasma exchange was superior to methylprednisolone for coming off dialysis

‘Severe renal’ - MEPEX n=151 Jayne, JASN 2007

Plasma exchange – renal survival (creatinine> 500) Jayne, JASN 2007

Relapse risk Booth, Am J Kid Dis 2002

Azathioprine vs. prolonged oral cyclophosphamide

ANCA and relapse ► 128, PR3-ANCA + ► Oral CYC 2 years or CYC followed by AZA ► ANCA status at switch Slot, Arthritis Rheum 2005

Mycophenolate mofetil vs. azathioprine IMPROVE trial: Cumulative Incidence of Relapse Hiemstra,14th International ANCA workshop 2009

Prednisolone dosing ► Induction  60mg/day ► Reduce in steps to 10mg/day by 12 weeks ►  Remission maintenance 5-10mg/day   Continue to 12 months Attempt withdrawal

Steroid withdrawal and relapse (STAVE)

STAVE – Results

Drug toxicity Jayne, Kidney and Blood Pressure Res, 2003

Conclusions on standard therapies ► ► ► ► Early diagnosis improves outcomes Induction  Cyclophosphamide and high dose prednisolone (3-6 months)  IV cyclophosphamide effective  Maintenance AZA ≅ MTX: LEF, MMF alternatives  Lower dose prednisolone  Assess relapse risk Adverse events  Avoid leukopaenia, especially in elderly

Newer therapies, Biologic or non-Biologic?

► IVIg ► Anti-TNF ► Rituximab ► ATG ► Alemtuzumab ► Abatacept ► Mycophenolic acid   Mycophenolate mofetil Enteric coated MPA ► Leflunomide ► Deoxysperguali n

Rituximab for refractory vasculitis n = 63 Jones, Arthritis Rheum 2009

Randomised trial of rituximab vs. cyclophosphamide for renal vasculitis (RITUXVAS) Jones, ASN 2008

Randomised trial of rituximab versus cyclophosphamide in ANCA vasculitis RAVE ► 197 new (49%) or relapsing WG/MPA  Creatinine < 4.0mg/dl, no lung haemorrhage ► Randomised, double-blind  Rituximab 375mg/m2/wk x4 vs . oral CYC  Both with IV/oral prednisone, stop at 6 months ► Primary end-point   Remission and steroid withdrawal at 6 months Non-inferiority design Stone J et al, ACR 2009

RAVE results ► Primary end-point 6 months ► 62% RTX, 55% CYC (p=0.2) ► Safety ► Similar AE rates  Absolute number AEs less with RTX (p=0.03) ► 18 month data end 2010 Stone J et al, ACR 2009

Suggested schema for the management of ANCA-associated vasculitis

Therapeutics and Clinical Risk Management 2010:6 253 –264

Conclusions ► Current approaches to treatment in induction and maintenance of AAV are well established (Table in earlier slide) ► The EULAR guidelines for the management of small and medium vessel vasculitis have recently been published and  The role of newer agents such as MMF is being defined by clinical trials EULAR: European League against Rheumatism, AAV : (ANCA)-associated vasculitides

Conclusions

(continued)

► The success and safety profile of rituximab in refractory disease has led to trials in maintenance and induction therapy which may see it recommended as standard practice, although  High cost may limit its use

Conclusions

(continued)

► The wide range of newer biologic agents now available brings huge possibilities for immunotherapy in relapsing or refractory disease  However, the rarity of AAV is a hindrance to developing an evidence base for practice ► Therefore, international cooperation and collaborative trials remain essential if patients are to receive appropriate, effective therapy

Conclusions

(continued)

► Renal vasculitis   Any size of renal vessel Necrotizing glomerulonephritis (ANCA) most common ► Pathogenesis  Role of ANCA  Neutrophil mediated endothelial toxicity

Conclusions

(continued)

► Treatment and outcomes    Dominated by severity at diagnosis - early

diagnosis

Relapse only minor issue – long-term

monitoring

Need for newer therapies