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Vasculitis is diagnosed by clinical and pathological criteria, not by ANCA alone.  Most inpatients have acute disease, for which the following guidelines are primarily intended.
 

Treatment of severe acute disease

Induction treatment is given to those with severe disease that needs to be controlled soon. Most receive cyclophosphamide and prednisolone. Those with the most severe disease receive plasma exchange in addition.  There is controlled trial evidence for the benefit of plasma exchange in patients who have serum creatinine >600 micromol/l or who require dialysis; it may be more generally valuable in 'rapid tempo' disease but that is unproven.  Other accepted indications would include life threatening pulmonary haemorrhage or worsening disease despite conventional therapy. 
 
 

Cyclophosphamide

Pulses of cyclophosphamide are generally preferred in the absence of evidence that oral cyclophosphamide is better. Oral cyclophosphamide is associated with higher cumulative doses and possibly greater short term and long term toxicity. The regimen suggested below is derived from the CYCLOPS protocol which showed non-inferiority of IV pulsed versus daily oral cyclophosphamide. It is slightly different from the protocols we are currently using in SLE.

  • Pulsed IV cyclophosphamide (CYC) should initially be given 2 weekly at time 0, 2 and 4 weeks. It is then given every 3 weeks at weeks 7, 10 and 13.
  • If a patient has not achieved remission at 3 months pulsed CYC should be continued every 3 weeks with doses given at weeks 16, 19, 22 and 25.
  • Dosage is determined from the following table:
 
Pulsed cyclophosphamide dose calculation
Age
Creatinine clearance (estimated by Cockroft-Gault equation)
>30
<30
<60
15 mg/kg/pulse 12.5 mg/kg/pulse
60-70
12.5 mg/kg/pulse 10 mg/kg/pulse
>70
10 mg/kg/pulse 7.5 mg/kg/pulse
 
Max dose per pulse is 1.2g

     

  • Mesna should be given with each dose as prophylaxis against haemorrhagic cystitis, orally or IV. If oral, the dose is the same as that of CYC (in mg). If IV, the dose is 40% that of the pulse of CYC (in mg) and given in the same bag as the CYC.
  • Ensure adequate patient hydration
  • Prevention of emesis: cyclizine 50 mg iv and ondansetron 8 mg iv is given 30 min prior to CYC. Supply both as oral formulations for patient to take home and take prn.  
  • Check FBC between days 10 and 14 after each pulse. If the total white cell count (WCC) nadir (i.e. the lowest WCC between two CYC pulses) is <3 x 109/L then reduce the dose of the next pulse by:
    • WCC nadir 1 - 2 x 109/L: reduce CYC dose of next pulse by 40 % of previous dose.
    • WCC nadir 2 - 3 x 109/L:  reduce CYC dose of next pulse by 20 % of previous dose.
    • The dose should be reduced even if the WCC just previous to the next pulse is >4 x 109/L
  • Check WCC on day of pulse or previous day. If WCC <4 x 109/l postpone until WCC >4 x 109/l. Check WCC count every 5-7 days in this case. Reduce dose of next CYC pulse by 20% if leucopenia has occurred.
  • If in remission by three months, or between three and six months, switch to azathioprine 2 mg/kg/day

Oral pulses of cyclophosphamide can be given if IV pulses are difficult - but not usually in the acute setting. See SLE for further information on the protocol for this.

Continuous oral cyclophosphamide is now used less commonly, but the protocol is: 2mg/kg ideal body weight, rounded down to nearest 50mg.  This is usually 150 or 100mg.  Use less in over-55s.  This dose is continued for three months unless (i) rapid fall in total WCC from 10 to less than 4.5 or (ii) WCC falls below 3.5.  The neutrophil count rather than the lymphocyte count determines the risk of infection.  Closer monitoring rather than substantially lower doses may be appropriate in severe renal impairment if patients have life-threatening disease.

Prednisolone

Corticosteroids are a vital part of therapy, but the cumulative dose of steroids is also a major determinant of the risk of infection.  The usual starting dose is 1mg/kg/day (usual max 80mg), reducing approximately in line with the following scheme:

Standard prednisolone regimen

60 mg OD

7 days

(or 1mg/kg)

45 mg OD

7 days

reduction in proportion to starting dose

30 mg OD

7 days

25 mg OD

7 days

20 mg OD

7 days

may be varied

17.5 mg OD

14 days

depending on

15 mg OD

until 12 weeks

clinical condition

 

Prophylactic treatment

  • Gastric protection: H2 antagonist or PPI e.g. Lansoprazole 30 mg PO daily until prednisolone <10 mg PO daily.  
  • Infection prophylaxis: Cotrimoxazole 480 mg PO daily for at least 3 months (often continued long-term in patients with Wegener’s granulomatosis and in those with ENT/lung disease)
  • Osteoporosis: see Osteoporosis prevention on steroids for more detailed discussion. A simple rule:
    • If eGFR >35 ml/min: bisphosphonate (e.g. alendronate 70 mg PO once per week) together with vitamin D and calcium supplement, eg. Adcal D3 two tablets PO daily
    • If GFR <35 ml/min: alfacalcidol (250 ng/day) and calcium supplement (eg Calcichew 2 tablets daily not with food)

Plasma Exchange

See above for indications. Daily 1 volume plasma exchanges for albumin x 5(-10).  Prevent depletion of clotting factors by monitoring closely with guidance from haematologists; either giving fresh frozen plasma 2 units at the end of exchange for all patients at risk of bleeding. Additonal therapy required for patients with pulmonary haemorrhage or other active bleeding. 
 

Methyl prednisolone

We rarely use this unless plasma exchange is contraindicated or other pressing reason, as it may confer a substantial additional risk of infection and cause delayed avascular necrosis.  500mg once daily x 3.
 

Maintenance treatment

Almost all patients with idiopathic RPGN and systemic vasculitis need maintenance immunosuppression. The need for maintenance treatment in patients with vasculitis is reviewed after one year, but after three months most patients require:

  • Azathioprine:         2-3 mg/kg/day to be started immediately after stopping cyclophosphamide
  • MMF is an alternative to azathioprine
  • Prednisolone:       10-15 mg OD depending on clinical condition (and usually reducing slowly)
     

Additional or alternative agents

Discussion is required before initiating any of these agents. 

Mycophenolate mofetil (MMF) is being tested as an alternative induction agent to cyclophosphamide.  It is widely accepted to be an effective maintenance agent as an alternative to azathioprine. Minimum dose should be 1g BD; in active disease, higher doses are standard. 

Methotrexate can be used to maintain remission in patients with Wegener’s, and is effective in other types of vasculitis and inflammatory arthritis. It is renally excreted and should be avoided if GFR <30, and used with caution in moderate renal impairment. Its onset of action is slow and its place is probably in chronic, grumbling disease but it can be used as induction therapy in extrarenal disease that is not life-threatening.  Start at 7.5mg once weekly followed 48h later by folic acid 5mg.  Start lower in renal impairment. Maintenance dose is usually 10-20mg once weekly.

Anti-TNF therapies – Anti-TNF therapy is currently reserved for those with evidence of persisting disease activity despite standard immunosuppression. Current drugs available are infliximab, an anti-TNF antibody and etanercept, a soluble p75 TNF receptor. We currently use infliximab 5mg/kg as an IV infusion given on weeks 0, 2, 6 and 10.  Infusion is given over 2 hours with monitoring of vital signs (pulse, bp, temp and respiratory rate) every 15 minutes. If patient responds they can continue with monthly infliximab injections long term. Before commencing therapy patients should be assessed for presence of latent tuberculosis by chest x-ray and tuberculin test.  Infection is the main adverse event and infusions should not be given if infection considered likely. 

Rituximab – see SLE

Anti-T cell antibodies – reserved for severe disease unresponsive to other treatments.  The risks when used after other failed therapies may be very high; discuss with local experts first. 

Campath 1H (alemtuzumab) (anti-CD52) is a humanised lymphocyte-depleting monoclonal antibody. Peripheral blood lymphocyte numbers return to normal but patients have very prolonged depletion of CD4 cells. It is given as an infusion with a total dose of 40-50mg over 2-5 days. 

Anti-thymocyte globulin (ATG) is a rabbit polyclonal antibody against activated lymphocytes. This is administered as a 10 day regimen as in renal transplantation (see detailed protocol there), with discontinuation of other cytotoxics or biological agents.

Treatment Algorithm

Note : where algorithm suggests cyclophosphamide treatment, pulsed therapy (see above) is now usually preferred.

 

Goodpasture's (anti-GBM) disease

Is mentioned here because of its similarity in presentation and treatment to small vessel vasculitis. Treatment should be cyclophosphamide-based and plasma exchange should used aggressively – daily for 10-14 days or until antibodies are suppressed.  Discuss no immunosuppression if renal damage irreversible and there is no lung haemorrhage. 

Cyclophosphamide: there is not substantial evidence on pulsed therapy, but because immunosuppression can usually be stopped completely at 3 months and recurrence is rare, the risk of cumulative toxicity is much reduced. We usually use daily oral cyclophosphamide in these circumstances.

Obtaining research samples before treatment may be extremely valuable – contact ANT/RGP or the research lab.
 
 

Trials 

Several trials of therapy are current under the umbrella of EUVAS. In Edinburgh, contact Dr Kluth for entry details. More information on our Trials page.
 

Patient information

Vasculitis - patient information from EdRenINFO

Immunosuppressive drugs and renal disease - patient information from EdRenINFO

Crescentic nephritis - patient information from EdRenINFO

Goodpasture's (anti-GBM) disease - patient information from EdRenINFO - simpler information is also available from a link at the top of the page.


 

 

Acknowledgements:   Neil Turner was the original main author for this page. It was revised in November 2006 and December 2007 by David Kluth and Neil Turner. The last modified date is shown in the footer.

 

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