Anti-neutrophil cytoplasmic antibody (ANCA) [Proteinase 3 (PR3) or myeloperoxidase (MPO)] - positive systemic necrotising vasculitis

Version: 3.1
Published: 24 April 2019
Condition for which Ig use is in exceptional circumstances only

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Specific Conditions
  • Anti-neutrophil cytoplasmic antibody (ANCA) (PR3 or MPO)-positive idiopathic rapidly progressive glomerulonephritis
  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss Syndrome)
  • Granulomatosis with polyangiitis (Wegener Granulomatosis)
  • Microscopic polyangiitis
Indication for Ig Use
  • Anti-neutrophil cytoplasmic antibody (ANCA) positive systemic necrotising vasculitis failing to respond to corticosteroids and cytotoxic immunosuppression
  • Relapse in ANCA positive systemic necrotising vasculitis resistant following response to Ig therapy
Level of Evidence Evidence of probable benefit – more research needed (Category 2a)
Description and Diagnostic Criteria Anti-neutrophil cytoplasmic antibody (ANCA) associated systemic necrotising vasculitides are life-threatening immune-mediated inflammatory diseases comprising one of four clinical syndromes:
  1. Granulomatosis with polyangiitis (Wegener granulomatosis)
  2. Microscopic polyangiitis
  3. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
  4. ANCA (PR3 or MPO)-positive idiopathic rapidly progressive glomerulonephritis
In these cases the ANCA specificity is directed against the neutrophil cytoplasmic antigens Proteinase 3 (PR3) and Myeloperoxidase (MPO). ANCA that lack MPO or PR3 specificity tend to be non-specific. Biopsy of affected tissue is required to establish the diagnosis.

Standard combinations of corticosteroids and cytotoxic immunosuppression are generally effective at controlling disease, but relapses are common.
Justification for Evidence Category The Biotext (2004) review found one randomised trial of 34 patients and one case series of seven patients with ANCA-associated systemic vasculitis (AASV). Different AASVs were represented in the studies. The Biotext (2004) review concluded that there is possible benefit in the treatment of AASV with IVIg if disease activity persists after standard therapy.
 
However, in recent years, there have been a number of randomised controlled trials demonstrating the effectiveness of  immunosuppressants and biologicals in achieving remission and treating relapsing and refractory disease. In particular, Rituximab is now considered a mainstay of treatment, and is now available on the Australian Pharmaceutical Benefits Schedule (PBS). The publication of the evidence based British Guidelines in 2014 for treatment of ANCA in adults, do not mention Ig therapy. It is recognized that Rituximab is more effective than Cyclosporine in refractory disease and if the patient has not had previous treatment with Rituximab, then it is the first choice. Ig therapy is only indicated in patients who have failed to respond to increased doses of immunosuppressants and a further trial of Rituximab, or in those in whom these therapies are contraindicated.
Diagnosis Requirements

A diagnosis must be made by an Immunologist, Nephrologist or a Rheumatologist.
Qualifying Criteria for Ig Therapy
Anti-neutrophil cytoplasmic antibody (ANCA) positive systemic necrotising vasculitis failing to respond to corticosteroids and cytotoxic immunosuppression
This indication should be used for new patients and those that have never received Ig therapy for this indication.  For responding patients who have relapsed after previous Ig therapy please use the indication Relapse in Anti-neutrophil cytoplasmic antibody (ANCA) positive systemic necrotising vasculitis resistant following response to Ig therapy.
 
  • Active MPO or PR3 positive vasculitis confirmed by serology and an ANCA–test result above the normal reference range
AND
  • Persistent active disease as assessed by at least two reactive indicators of: Birmingham vasculitis activity score (BVAS) version 3 (v3), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
AND
  • Persistent disease despite standard corticosteroid therapy for at least six months
     
  • OR
  • Corticosteroid therapy is contraindicated or has resulted in unacceptable side effects or significant toxicity
AND
  • No response at least three months after a trial of treatment with Rituximab
  • OR
  • Rituximab is contraindicated
AND
  • At least two other immunosuppressant agents have been trialled in addition to corticosteroids and Rituximab
  • OR
  • Immunosuppressant medication is contraindicated or has resulted in unacceptable side effects or significant toxicity
Six months treatment is authorised for patients in the first instance. While review is not mandated for this condition,  reporting of clinical outcome data is strongly encouraged as demonstrated clinical response to Ig therapy is required for eligibility for further authorisation, should the patient relapse in the future.
Relapse in ANCA positive systemic necrotising vasculitis resistant following response to Ig therapy
This indication should be used for responding anti-neutrophil cytoplasmic antibody (ANCA) positive systemic necrotising vasculitis patients who have relapsed following previous treatment with Ig therapy. For new patients and those that have never received Ig therapy, please use the indication ANCA positive systemic necrotising vasculitis failing to respond to corticosteroids and cytotoxic immunosuppression.
 
  • Clinical improvement in response to six months of Ig treatment was demonstrated previously as measured by a reduction in at least one of ESR, CRP or ANCA level or BVAS version 3 (v3) or another indicator of active disease compared to pre-treatment levels
AND
  • Current evidence of a relapse of active necrotising vasculitis as measured by reactivity in at least one of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ANCA level, Birmingham vascular activity score (BVAS) Version 3 (v3) or another indicator of active disease
AND
  • Unresponsive to previous Rituximab therapy
  • OR
  • Rituximab is contraindicated
AND
  • At least two other immunosuppressant agents have been trialled in addition to corticosteroids and Rituximab
  • OR
  • Immunosuppressant medication is contraindicated or has resulted in unacceptable side effects or significant toxicity
Six monthly review by a rheumatologist, immunologist or nephrologist is required to assess evidence of clinical benefit. Once the patient has been in clinical remission for two years after relapse, cessation of Ig therapy should be considered.
Exclusion Criteria First-line or initial treatment for ANCA
Review Criteria for Assessing the Effectiveness of Ig Use
Anti-neutrophil cytoplasmic antibody (ANCA) positive systemic necrotising vasculitis failing to respond to corticosteroids and cytotoxic immunosuppression
Six months treatment is authorised for patients in the first instance. While review is not mandated for this condition,  reporting of clinical outcome data is strongly encouraged as demonstrated clinical response to Ig therapy is required for eligibility for further authorisation, should the patient relapse in the future.

Clinical effectiveness of Ig therapy may be assessed by:
 
  • Reduction in at least one indicator of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, ANCA Level or Birmingham vasculitis activity score (BVAS) reduced by 50 percent or more, or other indicator of active disease compared to the qualifying value
Relapse in ANCA positive systemic necrotising vasculitis resistant following response to Ig therapy
Six monthly review by a rheumatologist, immunologist or nephrologist is required to assess evidence of clinical benefit. Once the patient has been in clinical remission for two years after relapse, cessation of Ig therapy should be considered.
 
Clinical effectiveness of Ig therapy may be assessed by:
 

On review of the initial authorisation period

  • Reduction in at least one indicator of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, ANCA level or Birmingham vasculitis activity  score (BVAS) or other indicator of active disease compared to the qualifying value for this indication
  • AND
  • Improvement in clinical symptoms in response to Ig treatment

On review of a continuing authorisation period

  • Stabilisation of at least one indicator of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, ANCA level or Birmingham vasculitis activity  score (BVAS) or other indicator of active disease compared to the previous review score
AND
  • Improvement or stabilisation in clinical symptoms compared to previous review
AND
  • A trial of Ig weaning towards cessation of Ig therapy is planned following two years in remission or a reason is provided as to why a trial is not planned
Dose
Anti-neutrophil cytoplasmic antibody (ANCA) positive systemic necrotising vasculitis failing to respond to corticosteroids and cytotoxic immunosuppression
  • Induction Dose (IVIg) - 2 g/kg in 2 to 5 divided doses
  • Maintenance Dose (IVIg) - 0.4-1g/Kg 4 to 6 weekly.
The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.
 
Refer to the current product information sheet for further information on dose, administration and contraindications.
 Dose Calculator
Relapse in ANCA positive systemic necrotising vasculitis resistant following response to Ig therapy
  • Induction Dose (IVIg) - 2 g/kg in divided doses
  • Maintenance Dose (IVIg) - 0.4-1g/Kg 4 to 6 weekly.
The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Refer to the current product information sheet for further information on dose, administration and contraindications.
 Dose Calculator
Bibliography
Biotext 2004, ‘Summary data on conditions and papers’, in A systematic literature review and report on the efficacy of intravenous immunoglobulin therapy and its risks, commissioned by the National Blood Authority on behalf of all Australian Governments, pp. 248–50. Available from: https://www.blood.gov.au/system/files/A-systematic-literature-review-and-report-on-the-efficacy-of-IVIg-therapy-and-its-risks.pdf

Foster, R, Rosenthal, E, Marques, S, et al 2006, ‘Primary systemic vasculitis: treatment of difficult cases’, Lupus, vol. 15, no. 3, pp. 143–7. https://www.ncbi.nlm.nih.gov/pubmed/16634367

Jayne, DR, Davies, MJ, Fox, CJ, et al 1991, ‘Treatment of systemic vasculitis with pooled intravenous immunoglobulin’, Lancet, vol. 337, no. 8750, pp. 1137–9

Jayne, DR & Rasmussen, N 1997, ‘Treatment of antineutrophil cytoplasm autoantibody-associated systemic vasculitis: initiatives of the European Community Systemic Vasculitis Clinical Trials Study Group’, Mayo Clinic Proceedings, vol. 72, no. 8, pp. 737–47. http://www.mayoclinicproceedings.org/article/S0025-6196(11)63594-5/abstract

Jayne, DR, Chapel, H, Adu, D, et al 2000, ‘Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity’, Quarterly Journal of Medicine, vol. 93, no. 7, pp. 433–9. https://www.ncbi.nlm.nih.gov/pubmed/10874052