Vasculitis (and anti-GBM disease)

Edinburgh vasculitis clinic

In Edinburgh, most patients with ANCA vasculitis are managed by the Edinburgh Vasculitis Service, embedded within the Department of Renal Medicine.  Some patients with small-vessel vasculitis are managed in other specialty services (rheumatology, respiratory, ENT).  Patients with large-vessel vasculitis are usually managed by rheumatology.

 

Classification and diagnosis

Vasculitis is a clinicopathological diagnosis, taking into account clinical features, histology and laboratory data including ANCA titres.  Vasculitis can be classified according to the size of the affected vessels (large-, medium-, small) and according to whether there is immune complex deposition evident on histology specimens (immune complex vs. “pauci-immune” vasculitis).  We have published our general approach to the diagnosis of ANCA vasculitis.

These pages predominantly refer to the management of ANCA-associated vasculitis.

 

Management of ANCA vasculitis

Overall approach

Broadly, management involves immunosuppression in two phases – induction and then maintenance of disease remission –  supported by adjunctive therapies aimed at reducing cardiovascular, infective and metabolic complications.  Treatment is guided by a strong evidence base, derived from reasonably large RCTs.  We follow consensus guidelines from the BSR and EULAR.

There is no single therapeutic regime that is suitable for all patients.  Treatment should be individualised, taking into account disease and patient characteristics and patient preferences.   Patients should be managed by a specialised vasculitis service.  The information below provides an indication of typical treatment regimes but should not be used as a blanket “protocol” to dictate management.

 

Induction immunosuppression

Induction immunosuppression usually entails:

  • for organ- or life-threatening disease: oral prednisolone in combination with IV cyclophosphamide or IV rituximab (and sometimes also plasma exchange)
  • for less severe disease: oral prednisolone plus oral MMF or methotrexate

 

Prednisolone

Corticosteroids can be a vital part of therapy, but the cumulative steroid dose is also a major determinant of the risk of infective and metabolic complications.  Our “standard” regime is illustrated below; this is always tailored to the individual patient.  (For example, frail elderly patients usually receive a lot less steroid and sometimes no steroid at all.) Other centres use IV methylprednisolone (500 mg x3); we almost never use this due to the high risk of infection and avascular necrosis and because of a lack of any proven benefit.

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 14 days clinical condition
12.5 mg OD 14 days
10 mg OD then wean relatively slowly
Cyclophosphamide

We use pulsed IV cyclophosphamide, using this prescription.

A reasonable dose is estimated from patient age and creatinine clearance (Cockroft-Gault); this is often revised (usually downwards) to account for other patient and disease characteristics.  Provision of IV Mesna and anti-emetics is detailed in the prescription chart as is a schedule for monitoring the FBC during therapy.  The lifetime risk of cancer after cyclophosphamide therapy is related to the cumulative dose; the risk begins to rise with  cumulative doses exceeding 10g.

Historically, continuous oral cyclophosphamide was preferred and in fact is still used by some centres.  There is a high risk of inducing neutropaenia and serious infective complications.  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.

 

Rituximab

We use Truxima, following this prescription and this infusion protocol.  (Our previous Mabthera prescription is here.)

Prior to therapy, check immunoglobulin levels, viral hepatitis serology (in particular because rituximab has been associated with re-activation of hepatitis B) and make a clinical risk assessment as to the clinical likelihood of latent TB.  Check an interferon gamma release assay in selected patients.

The standard dose for induction therapy is 1g x2, given 14 days apart.  Again, this is individualised to account for disease and patient characteristics.

 

 

Plasma Exchange

Historically, this was used relatively frequently in severe disease.  However in the PEXIVAS trial, plasma exchange did not reduce the incidence of death or end-stage kidney disease in ANCA vasculitis so it is now used rarely.  There may still be a role for plasma exchange in highly selected patients.  Typically daily exchanges for 5 days then alternate day exchanges for a further 2 or 3 exchanges.  Careful monitoring of coagulation parameters and use of FFP / cryoprecipitate is often necessary in patients with alveolar haemorrhage and in patients who have had a recent kidney biopsy.

 

MMF

Used for less severe disease; usually 1g bd.  Prescriber and patient must be aware of teratogenicity.

 

Maintenance immunosuppression

Most patients benefit from maintenance immunosuppression. This is usually continued for at least 18 months. Again, this is highly individualised.  The options are:

  • Prednisolone:  usual long-term maintenance dose is 5 mg od; complete withdrawal is advisable in most patients but may not be possible in all
  • Azathioprine:  2-3 mg/kg/day (usually preferred after cyclophosphamide induction)
  • MMF: usual long-term maintenance dose is 500 mg bd
  • Methotrexate: usually preferred in ENT disease.  It is excreted by the kidneys 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 extra-renal 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.
  • Rituximab: can be used as maintence monotherapy (or in combination with other agents).  Standard maintenance dose is 1g every 6 months.

 

Adjunctive therapies

In patients on corticosteroids:

  • peptic ulcer prophylaxis with H2 antagonist (e.g. ranitidine 150 mg bd) or PPI (e.g. lansoprazole 30 mg od) continued until prednisolone < 10 mg daily
  • osteoporosis prophylaxis with calcium and vitamin D supplements and / or a bisphosphonate: e.g.
    • give calcium and vitamin D in all (AdcalD3 two tablets daily if GFR > 30; alfacalcidol 250 ng plus calcichew two tablets daily if eGFR < 30)
    • if > 65 or prior fragility fracture: give bisphosphonate (e.g. alendronate 70 mg weekly if GFR < 30) and don’t request DEXA as therapy should be given regardless
    • if < 65 with no prior fragility fracture: request DEXA as urgent (and in females, start empirical alendronate pending DEXA result)

In all patients:

  • pneumocystis prophylaxis with co-trimoxazole 480 mg po daily continued for at least 12 months (and often continued indefinitely in granulomatous lung / ENT disease)
  • for patients who are intolerant of co-trimoxazole (e.g. with rash), usually attempt co-trimoxazole desensitisation as per this regime

 

In most patients:

  • cardiovascular risk reduction with lifestyle measures, statin, RAS inhibitors

 

Other issues / FAQs

Infections

See above for notes on screening for pneumocystis prophylaxis and screening for viral hepatitis and latent TB.

Check VZV serology at presentation.  If VZV seronegative then do not vaccinate (because this is a live vaccine) but do counsel patient and give VZIg in the event of contact risk.

If suspected latent TB then may need anti-tuberculous prophylaxis (e.g. isoniazid for 6 months).

Advise against swimming for first 3 months (or for duration of CYC) and thereafter encourage this for cardiovascular benefits.

Vaccinations
  • no live vaccines until off immunosuppression for 3 – 6 months (risk of disseminated viral disease)
  • avoid vaccines 4 weeks before and 4 months after Rituximab (risk of non-response)
  • encourage annual flu vaccine in all
  • encourage pneumococcal vaccine in all
Reproductive health

Counsel patients re: risk of infertility / teratogenicity with cyclophosphamide / azathioprine / MMF.  Consider cryopreservation of sperm / ovarian tissue / embryos.  Alternatively consider medical ovarian protection.

After cyclophosphamide, should have annual cervical smear for 3 yrs and then revert to UK national screening program.

 

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.

Patient information

 

Acknowledgements:   Neil Turner was the original main author for this page. It was revised in December 2007 by David Kluth and Neil Turner and in July 2020 by Robert Hunter. The last modified date is shown in the footer.