RENAL VASCULITIS(AAV)

Dr Rajesh Jhorawat

Nephrology, SMS

Land mark steps..

In 1808, Willan- distinguished purpura caused by infections from non-infectious purpura

Henoch and his teacher, Schönlein, described a broad spectrum of signs and symptoms that were associated with purpura, and with small vessel vasculitis

In 1866, Kussmaul and Maier described “periarteritis nodosa” later changed to “polyarteritis nodosa”

In 1936, Friedrich Wegener, a German pathologist, described three patients with necrotizing granuloma

In 1954, Goodman and Churg wrote a detailed description of “Wegener´s granulomatosis” (WG)

In 1970s, Fauci and Wolff introduced treatment with cyclophosphamide and corticosteroids for WG

In 1985, DeRemee published a report on the benefits of using cotrimoxazole (trimethoprim/ sulfamethoxazole) in WG

In 1985, Van der Woude et al who reported autoantibodies(ANCA) sensitive and specific for the WG

Vasculitis

INFLAMMATION OF BLOOD VESSEL

CLASSIFICATION OF VASCULITIS

1990- American College of Rheumatology (ACR) Classification Criteria

1994- Chapel Hill Consensus Conference (CHCC)

European Medicines Agency developed a stepwise lgorithm for vasculitis in 2007

CHCC definitions were revised in 2012

• ANCA testing not included

• PAN and MPA put togather

•Size of blood vessel (tissue Bx)•PAN and MPA seperated•ANCA suggested•AAV- WG, CSS, MPA

•ACR•Lanham crietria for CSS•ANCA•CHCC defination

Large vessels are the aorta and its major branches and theanalogous veins.

Medium vessels are the main visceral arteries and veins and their initial branches

Small vessels are intraparenchymal arteries,arterioles, capillaries, venules, and veins

ANCA-associated Vasculitis (AAV) Antineutrophil cytoplasm antibody (ANCA)–

associated vasculitis (AAV) is a group of multisystem diseases

Characterized by a pauci-immune small-vessel vasculitis with presence of circulating autoantibodies

Annual incidence of 20 per million Outcomes are often poor with a mortality of

25% at 5 years. Renal involvement is frequently seen and is

strongly associated with outcomes

ANCA-associated Vasculitis (AAV)

But newer insights for classification have emerged from large cohort and genetic studies esp. with two recent studies

Mahr et al Lyons et al.

ANCA and other antibodies

Antineutrophil cytoplasmic autoantibodies (ANCA) are a group of antibodies that react with cytoplasmic antigens in human neutrophils

These antibodies originally reported in 1964 and the first report linking these antibodies to disease was in 1982(Davies et al)

About 90% of patients with small-vessel vasculitis or pauci-immune NCGN have ANCA

The major autoantigens of ANCA are MPO and PR3.

MPO-ANCA is the predominant serotype in MPA patients, whereas PR3-ANCA is usually found in GPA.

True dual positivity is rare and raises suspicion of a drug-induced vasculitis.

Methods of Detection

IIF(screening)

ELISA(specificity)

Indirect Fluorescent Assay (IFA) In the immunofluorescent test for ANCA, several

patterns of cellular staining may be seen Two major patterns of staining have been

described and well characterized when ethanol-fixed neutrophils are used in the immunofluorescent ANCA test1. Cytoplasmic pattern called C-ANCA, are usually

directed against a serine protease, Proteinase 3 (PR3)

2. Perinuclear pattern called P-ANCA, are usually due to antibodies directed against myeloperoxidase (MPO)

C-ANCA P-ANCA

FIXATIVE PR3 MPO

ETHANOL CYTOPLASMIC PERINUCLEAR

FORMALIN CYTOPLAMIC CYTOPLASMIC

•Selected cohorts studied•Disease extent and activity at the time of serum sampling•Criteria used for setting the diagnoses•Way positive cutoff values for the assays used have been set

ANCA TESTING- CLINICAL USE DIAGNOSIS, PROGNOSIS, AND FOLLOW-UP

Most experts on vasculitis agree that the level of PR3-ANCA and MPO-ANCA is higher in active and/or extensive phase of the disease

PR3-ANCA and MPO-ANCA have some influence on the development of clinical features. Renal and respiratory involvement in PR3-ANCA Renal limited involvement is more often in MPO-

ANCA Patients positive for PR3-ANCA suffered more

frequent relapses than those positive for MPO-ANCA.

AAV- other Autoantibodies

These different autoantibodies are likely to reflect mechanisms operating in the inflammatory events and may even be part of an

orchestrated attackon the endothelium and basement membrane

Directed to small vessel ECs

Idiopathic AAV and in drug-induced vasculitis

Increase level is observed in relapse

Induce adhesion molecule expression and increased cytokine secretion

Don’t cross react and fluctuate independently with ANCA

Autoantibodies to the a3-domain of type IV collagen

Observed co-occurrance with ANCAs (esp. with anti-MPO)

co-occurrence with ANCAs influence outcome

Anti–endothelial cell antibodies (AECA)

Antibodies to Glomerular Basement Membrane( Anti-GBM)

Rare Anti–b2-glycoprotein 1,

anticardiolipin, or the lupus anticoagulant

With ACA more extensive and more severe disease

In Drug-induced vasculitis, antiphospholipid antibodies of the IgM class

Antiphospholipid Autoantibodies

Pathology

Basic leasion- segmental fibrinoid necrosis, often accompanied by leukocyte infiltration and leukocytoclasia (leukocyte fragmentation)

Patients with pauci-immune small-vessel vasculitis also may have renal arteritis, most often affecting interlobular arteries and medullary angiitis affecting the vasa recta

The medullary angiitis may be severe enough to cause papillary necrosis

Clinical Manifestations(AAV)

Treatment

Without therapy, ANCA vasculitis with GN is associated with very poor outcomes

Treatment with corticosteroids and cyclophosphamide has dramatically improved the short- and long-term outcomes of ANCA vasculitis associated with systemic disease.

Treatment with immunosuppressive therapy is therefore considered indicated in all cases of ANCA vasculitis and GN

Induction trials in AAV

Treatment

Rare possible exception relates to patients with severe kidney-limited disease, in the absence of extrarenal manifestations of small-vessel vasculitis

OR Patients with severe pauci-immune

NCGN requiring dialysis,

TreatmentBenefit/Risk

of Tx

Evidence- study-1

Study 2

Maintenance Therapy

Transplantation in AAV

Future option in AAV

THANK YOU

An increased prevalence of thromboembolic disease occurs in AAV, and autoantibodies have now been described to plasminogen and tissue plasminogen activator in the sera of one quarter of PR3-ANCA-positive AAV patients.

The presence of antiplasminogen antibodies correlated with venous thrombosis and with the severity of renal vasculitis

GENETICS AND THE ENVIRONMENT

Evidence for a genetic contribution in AAV has been increasing with familial associations and study of candidate genes, especiallyHLA DPB1*0401in European GPA patients.

Associations with HLA-DP, SERPINA1, and PRTN3 were identified for GPA. SERPINA1 encodes for a-1 antitrypsin and PRTN3 encodes for PR3.

An association with HLA-DQ was identified for MPA.

Interestingly, the genetics were more strongly associated with ANCA specificity (MPO-/PR3-ANCA) than clinical diagnosis (MPA/GPA).

Associations with environmental factors, such as air pollutants, infections, and drugs, have also been associated.

Silica is a well-known air pollutant contributing to many autoimmune diseases including AAV.

Peptides from Staphylococcus aureus have strong homology with peptides from complementary PR3, and Staphylococcus aureus infection has been associated with initiation and relapse of GPA

The anti-hLAMP-2 antibody also has 100% homology to FimH in Gram-negative bacteria.

In 2011, a Japanese group revealed that MPO-ANCA– activated glomerular endothelial cells directly in a murine model. They identified a new target antigen of MPO-ANCA, moesin, on the glomerular endothelium.

Moesin has partial amino-acid sequence homology with an epitope of MPO-ANCA

They found a high prevalence of anti-moesin antibodies in MPA patients

Cocaine use has caused several vasculitis syndromes including AAV, recently associated with contamination of cocaine by levamisole.

Propylthiouracil (PTU) is the most frequent cause of drug-induced AAV (especially MPA) The finding of multiple autoantibodies is more common in drug-induced than primary AAV, suggesting a dysregulation of self-tolerance.

HISTOPATHOLOGY

AAV often affects the kidneys and is the most common cause of rapidly progressive glomerulonephritis.

Renal involvement is an important predictor of increased mortality risk and morbidity in AAV, and renal biopsy aids in both diagnosis and prognosis.

An outcome-based classification of ANCA-associated glomerulonephritis histology has been developed to formalize the predictive value of the renal biopsy.

A validation study with 100 renal biopsies from AAV patients revealed that the classification was an independent predictor for estimated GFR after 1 year and 5 years.

Although the ‘Focal’ class showed good preservation of renal function and the ‘Crescentic’ class a good chance for renal recovery, the ‘Mixed’ and ‘Sclerotic’ classes had, respectively, intermediate and high risks of progression to end-stage renal disease.

T-cell tubulitis was an independent predictor for estimated GFR after 12 months and tubular atrophy was an independent predictor for estimated GFR after 12 months and 24 months.

Another recent topic in histopathology is the involvement of the complement system, especially the alternative pathway.

Xinget al.,detected components of the alternative pathway, factor B, factor P, C3d, and membrane-attack complex, in glomeruli and small blood vessels in kidney biopsy specimens from AAV patients

Treatment

The current treatment for AAV has been optimized by randomized controlled trials performed over the last 20 years

It is not curative but aims to control disease activity in a 3- to 6-month induction phase of high-dose glucocorticoid and daily oral or intravenous-pulsed cyclophosphamide that is effective in 80–90%.

Despite maintenance therapy of low-dose glucocorticoid and azathioprine or methotrexate, at least 10% of patients relapse each year

Induction trials

A rationale for B cell–targeted therapy in AAV has emerged from the presence of B cells at sites of inflammation, correlation of B-cell activation with disease activity in GPA, the efficacy of cyclophosphamide, which is a relatively B cell–specific immunosuppressant, and the contribution of ANCA to the pathogenesis.

Several case series and small prospective studies highlighted the efficacy of the anti-CD20 B cell–depleting monoclonal antibody, rituximab in refractory AAV.

Subsequently, two randomized trials evaluated rituximab for remission induction in new and relapsing patients.

Both the RAVE and RITUXVAS trials found similar remission rates for newly diagnosed patients between rituximab- and cyclophosphamide-based regimens when combined with high-dose glucocorticoid.

The RAVE trial also demonstrated superiority of rituximab for the subgroup treated for relapsing disease. However, no differences in safety were observed between the treatment groups, suggesting that glucocorticoid rather than cyclophosphamide is the major treatment-related cause of toxicity in AAV.

Rituximab is now indicated for relapsing AAV and newly diagnosed AAV when cyclophosphamide avoidance is desirable.

The pathogenicity of ANCA has contributed to a therapeutic rationale for plasma exchange in AAV

A metaanalysis of plasma exchange trials suggests a beneficial effect on the risk for end-stage renal disease but no effect on mortality

Current practice recommends plasma exchangefor those with severe renal disease or alveolar hemorrhage, although the evidence base in the latter indication is weak.

The PEXIVAS trial is examining the effect of plasma exchange on patients with a GFR below 50 ml/min or with severe alveolar hemorrhage

Maintenance therapy

Following control of features of vasculitis activity, the maintenance therapy aims to prevent vasculitis returning.

The WEGENT trial aimed to demonstrate the superiority of methotrexate over azathioprine, but adverse event rates were similar and relapse rates at 36 months were 50 and 47%, respectively.

The IMPROVE trial found mycophenolate mofetil was less effective compared with azathioprine for prevention of relapse, 55% vs. 38% after 39 months, with similar adverse event rates.

Maintenance Trials

Consequently, azathioprine or methotrexate, with or without low-dose glucocorticoid, is the preferred maintenance agents.

Recently, Smith et al. published a retrospective study, which revealed that a 2-year fixed interval routine rituximab therapy reduced relapse rate in relapsing AAV patients treated with rituximab.

This subject will be further studied in the

ongoing RITAZAREM trial

EGPA

EGPA has been excluded from most AAV trials. Recently, a French group examined the response to

glucocorticoids in nonsevere EGPA and glucocorticoids, as well as cyclophosphamide in severe EGPA.

Relapse rates in nonsevere EGPA are high if treated with glucocorticoids alone and studies of combinations with other immunosuppressants are needed.

Similarly, only anecdotal data exist for the role of rituximab in EGPA.

Two, small, open-label studies of an antiinterleukin-5 antibody, mepolizumab, have reported goodeffects in EGPA

OUTCOME

Long-term outcome studies by the European Vasculitis Society cohort with 535 AAV patients with a median of 5.2-year follow-up reported cumulative survival rates at 1 and 5 years of 88 and 78%, respectively.

Frequent causes of death within the first year were infection (48%) and active vasculitis (19%), and those after 1 year were cardiovascular disease (26%), malignancy (22%), and infection (20%).

In the same cohort, 38% of 535 patients experienced a relapse, and the relapse was more common in PR3-ANCA-positive patients.

As to malignancy, only the risk of nonmelanoma skin cancer was increased in this cohort

The low increases in cancer risk compared with previous studies might reflect short follow-up or lower exposure to cyclophosphamide in current protocols.

The French Vasculitis Study Group also showed similar results in their study for urotoxic adverse events .The risk of bladder cancer in AAV was low in an intravenous-pulsed cyclophosphamide group and a group diagnosed after 1998.

Longer follow-up is necessary because of the late development of malignancy.

Newer Therapeutic Agents

The proteasome inhibitor Bortezomib has demonstrated a stronger effect on autoantibody production than cyclophosphamide in experimental models.

The immunosuppressive agent gusperimus proved efficacy in controlling disease activity in two nonrandomized trials of refractory or relapsing GPA.

The anti-CD52 pan lymphocyte–depleting antibody, alemtuzumab, has led to sustained treatment-free remissions in AAV, but it is strongly immunosuppressive and is associated with severe adverse events in the elderly and those with renal failure.

CONCLUSIONS

The classification of vasculitis has been further revised and new genetic associations are likely to drive more changes in how vasculitis is subgrouped.

The discovery of newer autoantibodies raises the potential for newer biomarkers of clinical utility, as well as inspiring pathogenetic studies.

Rituximab is now firmly established in the treatment of ANCA vasculitis, and further innovations permitting reduced immunosuppressive and glucocorticoid exposure are in development.

Much of the recent progress has developed from the creation of international collaborative networks permitting consensus approaches and large-scale clinical studies.