Granulomatosis with polyangiitis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

severe (life/organ-threatening) disease: remission induction

1st line – high-dose corticosteroid

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1st line –

high-dose corticosteroid

Most patients are treated with corticosteroids, typically prednisolone. High-dose methylprednisolone is frequently given intravenously for 3 to 5 days prior to starting oral prednisolone.[37]

The initial corticosteroid dose is typically maintained for a period of 1 month, with slow tapering thereafter. As there is no evidence-based approach to corticosteroid tapering, this proceeds according to physician preference, risk of toxicity, disease severity, and patient characteristics. Typically given for a period of 3 to 6 months to induce remission.[48]

Minimising corticosteroid toxicity is a key element of management of granulomatosis with polyangiitis (GPA) (formerly known as Wegener's granulomatosis). One trial found that a reduced-dose regimen was non-inferior to the standard dose regimen (in terms of development of end-stage kidney disease or death) and resulted in 60% less corticosteroid exposure and a lower rate of serious infection at 1 year.[42] BMJ: plasma exchange and glucocorticoid dosing for patients with ANCA-associated vasculitis: a clinical practice guideline Opens in new window

Screening and preventive measures against corticosteroid-induced osteoporosis should be instituted, along with monitoring and treatment for other complications (e.g., hypertension, diabetes mellitus, dyslipidaemia).[44] See Osteoporosis.

Corticosteroid regimens may vary, and you should consult your local guidance for more information.

Primary options

methylprednisolone sodium succinate: 0.5 to 1 g intravenously every 24 hours for 3-5 days, followed by oral prednisolone

and

prednisolone: 1 mg/kg/day orally following methylprednisolone course, maximum 80 mg/day

Plus – immunosuppressant

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Plus –

immunosuppressant

Treatment recommended for ALL patients in selected patient group

An immunosuppressive agent is also required as corticosteroid monotherapy is not sufficient.[37][38][41]

First-line treatments in life/organ-threatening disease include cyclophosphamide or rituximab.[37][41] Patients who do not respond to cyclophosphamide should typically be switched to rituximab and vice versa.[37]

The American College of Rheumatology recommends rituximab (where available) over cyclophosphamide for remission induction because rituximab is considered less toxic.[37] European guidelines recommend that either cyclophosphamide or rituximab may be used to induce remission in life- or organ- threatening vasculitis.[38]

Randomised controlled trials have demonstrated that rituximab is non-inferior to cyclophosphamide for induction of remission in severe GPA and may be more effective in the setting of a severe disease relapse.[46][47] Prolonged cyclophosphamide therapy is associated with potentially life-threatening adverse effects, including myelotoxicity, infection, and malignancy.[10]

The choice between regimens may be influenced by factors including the patient's risk of relapse, compliance with treatment and monitoring schedules, fertility issues, and potential susceptibility to other adverse effects of cyclophosphamide.[41] If intravenous cyclophosphamide is used, the protocol should incorporate intravenous fluids and mesna (a uroprotective agent) to minimise bladder toxicity. To reduce the risk of toxicity from oral cyclophosphamide, it should be taken in the morning and a liberal fluid intake maintained throughout the day. Full blood count and urinalysis should be monitored regularly, in accordance with local protocols. The dose of cyclophosphamide should be reduced in those with severe renal failure and in older patients.

Use of cyclophosphamide can cause infertility in both men and women. Use of leuprorelin to suppress ovarian function during cyclophosphamide treatment may help preserve fertility in women.[54] For male patients, sperm banking is advisable prior to cyclophosphamide use, although this may not be feasible with acute disease presentations.[54] Use of rituximab as a first-line therapy should be considered in patients where preservation of fertility is a concern.[38]

Patients who do not respond to an appropriate remission induction regimen should be evaluated for other comorbidities, such as infection and malignancy.[37]

Primary options

rituximab: 1000 mg intravenously once daily on days 1 and 15; or 375 mg/square metre of body surface area intravenously once weekly for 4 weeks

cyclophosphamide: 1-2 mg/kg/day orally; 15 mg/kg intravenously every 2 weeks for 3 doses, followed by 15 mg/kg every 3 weeks for at least 3 doses

Plus – supportive care

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Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

Prophylaxis against Pneumocystis jirovecii is indicated for all patients treated with rituximab or cyclophosphamide.[37] Prophylaxis should be considered for patients receiving moderate-dose glucocorticoids (>20 mg/day) in combination with methotrexate, azathioprine, or mycophenolate.[37] See Pneumocystis jirovecii pneumonia.

A saline nasal spray with or without a nasal antibiotic ointment should be instituted in all patients with sino-nasal manifestations. Involvement of an otorhinolaryngologist experienced in the management of the condition is advisable.

Consider – avacopan

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Consider –

avacopan

Additional treatment recommended for SOME patients in selected patient group

Avacopan (a complement 5a receptor antagonist) may be used as an adjunct to corticosteroids to reduce exposure to the corticosteroid in patients that are likely to have enhanced benefit compared with corticosteroid therapy (e.g., patients at higher risk of developing or having worse corticosteroid-related adverse effects and complications, or patients with active glomerulonephritis and rapidly deteriorating kidney function.[38][41][43]

Avacopan demonstrated efficacy comparable to prednisolone in one randomised clinical trial of 331 patients with ANCA-associated vasculitis, where it was used in combination with rituximab or cyclophosphamide.[43]

Primary options

avacopan: 30 mg orally twice daily

Consider – plasmapheresis

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Consider –

plasmapheresis

Additional treatment recommended for SOME patients in selected patient group

A large clinical trial demonstrated that plasmapheresis is not beneficial for the majority of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.[42] However, the addition of plasmapheresis may be considered in selected patients with particularly severe organ involvement (e.g., pulmonary-renal syndrome with respiratory failure requiring ventilation, and/or serum creatinine >435 micromol/L [>5.7 mg/dL]), but should be restricted to specialist centres.[52]

This treatment carries significant potential morbidity, including serious infection, catheter-related complications (e.g., thrombosis), haemodynamic instability, electrolyte disturbance, and coagulopathy.[37][53]

Consider – intravenous immunoglobulin (IVIG)

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Consider –

intravenous immunoglobulin (IVIG)

Additional treatment recommended for SOME patients in selected patient group

In patients with refractory disease, IVIG may be added to remission induction therapy with rituximab or cyclophosphamide to achieve disease control while waiting for remission induction therapy to become effective.[37] IVIG may be administered to patients with active GPA who are unable to receive any other immunomodulatory therapy.[37]

Primary options

normal immunoglobulin human: consult specialist for guidance on dose

Consider – local therapy for subglottic stenosis

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Consider –

local therapy for subglottic stenosis

Additional treatment recommended for SOME patients in selected patient group

Patients should be managed by an otolaryngologist with expertise in management of subglottic stenosis.[37] Systemic remission induction therapy is recommended for initial treatment of active, inflammatory subglottic stenosis.[37]

Local therapy with intralesional glucocorticoid injection and surgical dilatation should be considered for patients with subglottic stenosis that is longstanding, fibrotic, or unresponsive to systemic immunosuppressive therapy.[37][66] Local therapy and immunosuppressive therapy may be used concurrently for subglottic stenoses causing critical airway narrowing.[37]

Local therapy may need to be repeated at highly variable intervals. In the vast majority of cases this approach can obviate the need for tracheostomy or more radical surgical procedures.

Primary options

methylprednisolone acetate: consult specialist for guidance on intra-lesional dose

Consider – debulking surgery

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Consider –

debulking surgery

Additional treatment recommended for SOME patients in selected patient group

Debulking surgery may be considered rarely, in addition to remission induction therapy, if there is life- or organ-threatening compression (e.g., acute visual loss due to optic nerve compression by orbital pseudotumour).[37] Surgery should only be considered in conjunction with a centre of vasculitis expertise.

non-severe (non-life/organ-threatening) disease: remission induction

1st line – high-dose corticosteroid

Back

1st line –

high-dose corticosteroid

Most patients are treated with corticosteroids, typically prednisolone. High-dose methylprednisolone is frequently given intravenously for 3 to 5 days prior to starting oral prednisolone.[37]

Minimising corticosteroid toxicity is a key element of management of GPA. One trial found that a reduced-dose regimen was non-inferior to the standard dose regimen (in terms of development of end-stage kidney disease or death) and resulted in 60% less corticosteroid exposure and a lower rate of serious infection at 1 year.[42] BMJ: plasma exchange and glucocorticoid dosing for patients with ANCA-associated vasculitis: a clinical practice guideline Opens in new window Screening and preventive measures against corticosteroid-induced osteoporosis should be instituted, along with monitoring and treatment for other complications (e.g., hypertension, diabetes mellitus, dyslipidaemia).[44] See Osteoporosis.

Corticosteroid regimens may vary, and you should consult your local guidance for more information.

Primary options

methylprednisolone sodium succinate: 0.5 to 1 g intravenously every 24 hours for 3-5 days, followed by oral prednisolone

and

prednisolone: 1 mg/kg/day orally following methylprednisolone course, maximum 80 mg/day

Plus – immunosuppressant

Back

Plus –

immunosuppressant

Treatment recommended for ALL patients in selected patient group

An immunosuppressive agent is also required as corticosteroid monotherapy is not sufficient.[37][38]

For non-severe disease, including patients with glomerulonephritis without significant renal insufficiency (creatinine <132.6 micromol/L [<1.5 mg/dL]), treatment with rituximab is recommended by European guidelines, with methotrexate or mycophenolate considered as alternatives to rituximab.[38][49] In the US, methotrexate is considered first-line treatment for non-severe GPA patients, with rituximab, azathioprine, mycophenolate, or cyclophosphamide to be considered for patients who do not respond to methotrexate.[37]

Full blood count and complete metabolic panel should be monitored regularly in patients taking methotrexate, in accordance with local protocols. Adequate contraceptive measures are essential (male and female).[37] Administration of folic acid helps reduce other side effects of methotrexate such as stomatitis, hair loss, and gastrointestinal intolerance. If side effects occur despite use of folic acid, folinic acid may be used.

A randomised controlled trial comparing mycophenolate with cyclophosphamide for induction of remission demonstrated that mycophenolate was non-inferior to cyclophosphamide for induction of remission, but was associated with a higher relapse rate.[55]

Cyclophosphamide may be administered as daily oral or pulse intravenous therapy. Pulse intravenous cyclophosphamide is as effective as daily oral cyclophosphamide at inducing remission and is associated with lower cumulative cyclophosphamide exposure and fewer cases of leukopenia.[49][50] However, intravenous therapy has been associated with higher relapse rates than oral cyclophosphamide.[51] The choice between regimens may be influenced by factors including the patient's risk of relapse, compliance with treatment and monitoring schedules, fertility issues, and potential susceptibility to other adverse effects of cyclophosphamide.[41] If intravenous cyclophosphamide is used, the protocol should incorporate intravenous fluids and mesna (a uroprotective agent) to minimise bladder toxicity. To reduce the risk of toxicity from oral cyclophosphamide, it should be taken in the morning and a liberal fluid intake maintained throughout the day. Full blood count and urinalysis should be monitored regularly, in accordance with local protocols. The dose of cyclophosphamide should be reduced in those with severe renal failure and in older patients.

Patients who do not respond to an appropriate remission induction regimen should be evaluated for other comorbidities, such as infection and malignancy.[37][38]

Primary options

methotrexate: 7.5 to 25 mg orally/subcutaneously once weekly on the same day each week

rituximab: 1000 mg intravenously once daily on days 1 and 15; or 375 mg/square metre of body surface area intravenously once weekly for 4 weeks

Secondary options

mycophenolate mofetil: 1 to 1.5 g orally twice daily

cyclophosphamide: 1-2 mg/kg/day orally; 15 mg/kg intravenously every 2 weeks for 3 doses, followed by 15 mg/kg every 3 weeks for at least 3 doses

azathioprine: 1-2 mg/kg/day orally

Plus – supportive care

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Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

Consider – avacopan

Back

Consider –

avacopan

Additional treatment recommended for SOME patients in selected patient group

Primary options

avacopan: 30 mg orally twice daily

Consider – intravenous immunoglobulin (IVIG)

Back

Consider –

intravenous immunoglobulin (IVIG)

Additional treatment recommended for SOME patients in selected patient group

Primary options

normal immunoglobulin human: consult specialist for guidance on dose

Consider – local therapy for subglottic stenosis

Back

Consider –

local therapy for subglottic stenosis

Additional treatment recommended for SOME patients in selected patient group

Local therapy may need to be repeated at highly variable intervals. In the vast majority of cases this approach can obviate the need for tracheostomy or more radical surgical procedures.

Primary options

methylprednisolone acetate: consult specialist for guidance on intra-lesional dose

Consider – debulking surgery

Back

Consider –

debulking surgery

Additional treatment recommended for SOME patients in selected patient group

ONGOING

remission successfully induced

1st line – remission maintenance with corticosteroids and immunomodulatory therapy

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1st line –

remission maintenance with corticosteroids and immunomodulatory therapy

Rituximab is recommended as first-line treatment for remission maintenance for patients with severe life-threatening and non-severe GPA patients who have achieved remission with either rituximab or cyclophosphamide. Azathioprine or methotrexate may be considered as alternatives.[37][38][41] [ ]

Leflunomide may be considered for remission maintenance if a patient has contraindications to treatment with the other agents discussed above, develops intolerance to these agents, or experiences exacerbations of disease activity on standard treatments.[38]

If remission is successfully induced with methotrexate, azathioprine, or mycophenolate the same treatment should be continued for remission maintenance.[37][38] Cyclophosphamide should be used only for remission induction.

A low-dose rituximab regimen has been found to be superior to azathioprine in a population of patients with predominantly new-onset GPA, following remission induction with cyclophosphamide.[57][58][59] A subsequent study demonstrated that continued treatment with bi-annual rituximab infusions over 18 months was associated with a lower incidence of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis relapse, compared with standard maintenance therapy.[60] While some questions remain about the optimal dosing schedule, the cumulative experience with rituximab has led to its increasing use as first line for remission maintenance, particularly where it has been used for remission induction.[61]

Methotrexate and azathioprine are equally effective for remission maintenance.[62] Patients who must discontinue methotrexate due to intolerance in the absence of a disease flare should be switched to azathioprine for continued remission maintenance, and vice versa.

Mycophenolate has been considered as an alternative remission maintenance agent in GPA, based on initial uncontrolled studies. However, a randomised controlled trial demonstrated that it was inferior to azathioprine for remission maintenance in GPA.[63] Therefore, it should be reserved for patients who are refractory to and/or intolerant of methotrexate and azathioprine.[37]

The optimal duration of immunomodulatory maintenance therapy is uncertain, but therapy between 24 and 48 months after remission is generally recommended.[38] For patients who have already sustained one or more disease relapses, indefinite maintenance therapy is generally advised.

Patients continue on corticosteroids during remission maintenance, although a proportion of patients with well-controlled symptoms can be slowly tapered off.[38] A target dose of 5 mg/day of prednisolone by 4 to 5 months is recommended.[38] Low-dose corticosteroids may reduce the risk of relapse, but this must be balanced against the potential associated toxicity.[64]

Screening and preventive measures against corticosteroid-induced osteoporosis should be continued, along with monitoring and treatment for other complications (e.g., hypertension, diabetes mellitus, dyslipidaemia).[44] See Osteoporosis.

Primary options

prednisolone: 5 to 7.5 mg orally once daily

and

rituximab: 500 mg intravenously every 6 months; or 1000 mg intravenously every 4 months

Secondary options

prednisolone: 5 to 7.5 mg orally once daily

-- AND --

methotrexate: 7.5 to 25 mg orally/subcutaneously once weekly on the same day each week

azathioprine: 1-2 mg/kg/day orally

mycophenolate mofetil: 1 to 1.5 g orally twice daily

leflunomide: 10-20 mg orally once daily

Plus – supportive care

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Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

Consider – nasal reconstructive surgery

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Consider –

nasal reconstructive surgery

Additional treatment recommended for SOME patients in selected patient group

Nasal reconstructive surgery for patients with nasal septal defects and/or nasal bridge collapse may be considered after a period of sustained remission. Patients should be managed by an otolaryngologist with expertise in management of GPA.[37]

relapse following successful remission

1st line – further course of remission induction therapy

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1st line –

further course of remission induction therapy

Patients with disease relapses are treated according to the principles of remission induction therapy. However, the choice of therapies will be influenced by the efficacy and tolerability of previously used agents.[37]

The recommendation is that in order to limit long-term toxicities, cumulative lifetime cyclophosphamide exposure should not exceed 25 g.[65] Patients with a severe relapse that have reached, or are close to, that level of exposure should be treated with an alternative remission induction therapy such as rituximab.

To reduce treatment-related toxicities, it is essential that immunosuppressive therapy is used judiciously. Careful assessment of disease activity is crucial.

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Granulomatosis with polyangiitis

Treatment algorithm

severe (life/organ-threatening) disease: remission induction

high-dose corticosteroid

Primary options

immunosuppressant

Primary options

supportive care

avacopan

Primary options

plasmapheresis

intravenous immunoglobulin (IVIG)

Primary options

local therapy for subglottic stenosis

Primary options

debulking surgery

non-severe (non-life/organ-threatening) disease: remission induction

high-dose corticosteroid

Primary options

immunosuppressant

Primary options

Secondary options

supportive care

avacopan

Primary options

intravenous immunoglobulin (IVIG)

Primary options

local therapy for subglottic stenosis

Primary options

debulking surgery

remission successfully induced

remission maintenance with corticosteroids and immunomodulatory therapy

Primary options

Secondary options

supportive care

nasal reconstructive surgery

relapse following successful remission

further course of remission induction therapy