ANCA-Associated Vasculitis: AC ase Study

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					ANCA-Associated Vasculitis:
A Case Study
Scottish Paediatric Renal Urology Network
Dr Anne McGettrick
10th May 2010
   Review case

   Briefly discuss pulmonary vasculitides

   Discuss ANCA Associated Vasculitis

   Review rationale for and use of
    plasmapheresis in ANCA associated
Case Study
   15 year old girl
   History of haematemesis
   Intermittent vomiting over the previous year,
    possibly self induced
   One admission 1/12 previously 2+protein and
    2+blood in urine with URTI
   Clinically dehydrated in acute renal failure
   Creatinine >600
   Urea 19
Case Study
 Treated with iv fluids / high dose omeprazole
 Creatinine remained elevated despite
 Remained Oliguric

 Transferred to RHSC for nephrology review
 Prior to transfer, had developed an oxygen
  requirement and some increased WOB
    Case Study: Patient A
   On arrival: Fluid overloaded with signs of
    pulmonary oedema

   Admitted to PICU for non invasive ventilation,
    though rapidly progressed to ventilation

   ARF: Creat 643 / Urea 14.3 / K 6.5 :Vascath was
    inserted and commenced on haemofiltration
Case Study: Initial Course
During first night in PICU
 ◦ large pulmonary haemorrhage
 ◦ Difficult oxygenation sats in 80s
 ◦ V-V ECMO to achieve adequate oxygenation

History revisited
  ◦ haematemesis was more consistent with
  ◦ pulmonary-renal syndrome was suspected
  ◦ Autoantibodies to Neutrophil Cytoplasmic
    Antigens (ANCA) positive
  ◦ High levels of MPO ANCA antibodies
Case Study: Supportive therapy
 V-V ECMO 1/52
 HFOV and Nitric Oxide 1/52

 Haemofiltered as anuric
 Creatinine improved – mainly filtered for fluid
 Renal Biopsy: Severely damaged kidney with
  near total glomerular obliteration with evidence
  to suggest that there has been a recent
  crescentic glomerulonephritis
Case Study: Vasculitis
 Plasmafiltration – Eight courses in 1st week,
  while on Haemofilter and ECMO circuit

 High dose IV Methylprednisolone
 IV pulse Cyclophosphamide
 Rituximab therapy
Case Study: Respiratory
 Conventional ventilation 47 days – long slow
 Tracheostomy to facilitate long term ventilation
 Airway granulomata present at MLB
 Staph aureus pneumonia at time of febrile
 Discharged to ward after 63 days in PICU with
tracheostomy in situ
    Case Study: Renal Issues
 Intermittent haemodialysis as failed to wean from
haemofilter, initially daily
 Creatinine around 230, Urea 20-30
 Ongoing twice weeklyhaemodialysis
 Dry weight post PICU 61kg –admission weight

 Lots of education regarding fluid management &
renal diet…Social Issues
Case Study: Vasculitis
 Weaning regime of PO prednisolone
 Ongoing pulse iv cyclophosphamide, now 3-

 MPO levels decreasing serially
 ESR decreasing slowly
Case Study: Rash
Case Study: Current Issues
   Twice weekly haemodialysis, improving renal
   Ongoing Hypertension
   Tracheostomy reversal - ?ongoing airway
    granulomata – having MLB today
   Intermittent O2 requirement
   Neurophysio / rehab
   Ongoing Immunosuppression

   Social Issues & Discharge Planning
ANCA-Associated Vasculitis
   Otherwise known as:
    ◦ Wegener’s Granulomatosis
    ◦ Granulomatosis with polyangiitis (Wegener’s)

   Why change the name
    ◦ Wegener’s, Churg- Strauss, Bechet’s
    ◦ Dr Fredrich Wegener a pathologist in the
      Nazi party – working in Lodz a polish ghetto
      in which thousands died in WWII
Not this man
Pulmonary Vasculitides
   Characterised by cellular infiltration, infiltration
    and necrosis of blood vessel wall

   Either primary ie. autoimmune or secondary to
    infection, malignancy, drugs

   Primary vasculitides subgrouped according to
    small, medium or large vessels and the small
    (microscopic) group are further subdivided into
    syndromes associated with ANCA and those
    associated with immune complex deposition
Primary vasculitis                                Small-vessel vasculitis
                                                   Wegener granulomatosis
                                                   Microscopic polyangiitis
                                                   Churg-Strauss vasculitis
                                                  Medium-vessel vasculitis
                                                   Polyarteritis nodosa
                                                   Kawasaki disease
                                                  Larger-vessel vasculitis
                                                   Takayasu arteritis
                                                   Giant cell arteritis

Immune complex–mediated vasculitis                Goodpasture syndrome

                                                  Henoch-Schönlein purpura
Secondary vasculitis                              Infection
                                                  Malignancy (paraneoplastic)
                                                  Drug-induced vasculitis
                                                  Connective tissue diseases

                                                  Antiphospholipid antibody syndrome

                                                  Inflammatory bowel disease
                                                  Essential cryoglobulinemia

Table 1. The vasculitides
Data from Frankel SK, Cosgrove GP, Brown KK. Small vessel vasculitis of the lung. Chron Respir Dis 2005;2:75; Frankel SK, Cosgrove GP,
Fischer A, et al. Update in the diagnosis and management of pulmonary vasculitis. Chest 2006;129:452; Jennette JC, Falk, RJ. Small-vessel
vasculitis. N Engl J Med 1997;337:1512; Jennette JC, Falk R, Andrassay K, et al. Nomenclature of systemic vasculitides. Arthritis Rheum
Granulomatosis with polyangiitis
   Most common small vessel AAV

   Classically characterised by
    1. Upper respiratory tract disease
    2. Lower respiratory tract disease
    3. Renal Disease – Glomerulonephritis
Granulomatosis with polyangiitis
   Renal involvement occurs in 40% of patients at
    diagnosis and develops in 70-80% over the
    course of the disease

   Closely associated with circulating
    Autoantibodies to Neutrophil Cytoplasmic
    Antibodies (ANCA) with specificity for
    proteinase 3 (PR3) or myeloperoxidase (MPO)
Granulomatosis with polyangiitis
Histologic features
 Intense neutrophil-predominant inflammatory

   Segmental glomerular necrosis reflecting
    glomerular capillaritis

   Intraglomerular monocyte proliferation
    contributing to a pauci–immune, focal and
    necrotising crescentic glomerulomephritis
Granulomatosis with polyangiitis
Granulomatosis with polyangiitis
   75-95% of patients have resp tract
    involvement at diagnosis

   URT symptoms include: epistaxis; rhinitis;
    sinusitis; tracheal lesions, classic ‘saddle nose’

   LRT involvement: cough; haemoptysis; SOB;
    Chest pain; pulm infiltrates/ nodules or cavities
Granulomatosis with polyangiitis
Other target organs
 Skin (45-60%)
 Eyes (25-50%)
 Peripheral nervous system (10-30%)
 Musculoskeletal system (30-70%)
 Heart (5-15%) : conduction delay, endocarditis,
  cardiomyopathy, valvular disease, pericardial
  disease contribute disproportionately to
 Malaise, fever, anorexia and wt loss also
Treatment: Granulomatosis with polyangiitis

 Before introduction of Cyclophosphamide
  based therpeutic regimes, survival rates were
  20% at 2 years
 5 yr survival now approaches 80%
 Goals / Current Standard of Care
    ◦ Control disease activity rapidly to limit organ damage
    ◦ Minimise treatment related toxicity
    ◦ European Vasculitis Study Group (EUVAS) have
      devised a system of subgroupings based on severity of
 Granulomatosis with polyangiitis:Severity
Disease               European Vasculitis Study               Induction therapy
Severity              Group definition
Localised disease     Upper and/or lower resp tract           Methotrexate and steroid
                      disease without any other
                      systemic involvement or
Early Systemic        Any, without organ threatening or       Methotrexate or
disease               life threatening disease                Cyclophosphamide and
Generalised           Renal or other organ threatening        Cyclophosphamide and
disease               disease; serum creatinine level         steroid
Severe disease        Renal or other vital organ failure;     Cyclophosphamide and
                      serum creatinine level >500             steroid with plasma exchange

  Recent advances to achieve remission induction in antineutrophil cytoplasmic
  antibody-associated vasculitis: Harper, Lorraine: Current Opinion in Rheumatology. 22(1):37-
     42, January 2010.DOI: 10.1097/BOR.0b013e328331cfeb
Granulomatosis with polyangiitis:
Cyclophosphamide Treatment

   Pulse iv cyclophosphamide (15mg/kg every 2
    weeks for 1st 3 pulses then every 3 weeks) as
    effective as daily PO cyclophosphamide (2mg/kg
    daily) in inducing remission

   Pulse group 50% lower dose cyclophos

   Pulse group significantly fewer leucopaenic
Granulomatosis with polyangiitis: Rituximab
   Anti-CD20 monoclonal antibody

   Achieves B cell depletion

   In those with renal disease, ANCA falls
    predictably but at slower rate than disease

   Induction of remission associated with
    complete peripheral B cell depletion
Granulomatosis with polyangiitis: Plasma
   Removes circulating auto-antibodies and large plasma
    proteins including, cytokines, complement, coagulation
    factors and neutrophil enzymes

   Filtration or centrifugation of blood to separate plasma
    or other blood constituents and then replacement of
    plasma with a substitute –albumin

   Exchange of 1 to 1.5 plasma volumes removes 70-80%
    of the desired substance
Granulomatosis with polyangiitis: Plasma
   If a substance such as IgG auto-antibody is widely
    distributed in ECF there will be equilibration between
    extra and intra-vascular compartments, therefore
    repeated exchanges are necessary

   5-7 exchanges are required to remove 75% of
    antibodies from the body

   Associated with mild adverse events especially
    electrolyte disturbances eg hypocalcaemia
Granulomatosis with polyangiitis: Plasma
   World apheresis register reports adverse
    events in 5.7% of 838 patients with no related

   An analysis of 91,000 plasma exchanges in a
    Canadian series identified a 0.4% incidence of
    serious adverse events: TRALI; haemorrhage and
    anaphylaxis to blood products
Granulomatosis with polyangiitis: Plasma

   Danish 2010 RCT on Plasma Exchange (PLEX)
    for WG in adults

   4 groups (8 patients each)
    ◦ Plasma exchange +cyclophosphamide
    ◦ Plasma exchange + cyclophos and changed to
      cyclosporin A at 3/12
    ◦ Cyclophosphamide
    ◦ Cyclophosphamide and changed to cyclosporin A at
Granulomatosis with polyangiitis: Plasma
Renal outcomes
  ◦ At 1/12 no PLEX pts on HD or in renal

  ◦ Controls 6/16 in renal progression and 5/16
    on HD (p<0.05)

  ◦ Significantly lower ANCA titres in PLEX
    group after 1/12 which disappeared at 3/12
Granulomatosis with polyangiitis: Plasma
Renal Outcomes
  ◦ No significant difference in relapses between
    cyclophosphamide (8/13) and CYC A (10/18)

  ◦ No difference in relapses between PE and no PE

  ◦ No effect on mortality
To Summarise
   Complex multiorgan disease

   Most data from adults

   Immunosuppression with Plasma Exchange
    appears more effective than
    Immunosuppression alone
Any questions?

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