Granulomatosis with polyangiitis

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

Assessment and treatment of patients with granulomatosis with polyangiitis (GPA) (formerly known as Wegener's granulomatosis) should be undertaken only in specialised centres by physicians experienced in the management of the condition, and a multidisciplinary approach should be used.[38]

Medical treatment of GPA is usually considered in two stages: remission induction and remission maintenance.[39]

Patients with untreated systemic GPA have a median survival of 5 months, underlining the importance of early aggressive therapy.[40]

Remission induction

All patients with active GPA are treated with corticosteroids, typically prednisolone. However, corticosteroid monotherapy is not sufficient and a second immunosuppressive agent is required.[37][38][41] Disease severity is the principal determinant of the most appropriate additional agent.[37]

Minimising corticosteroid toxicity is a key element of management of GPA. The recommended dosing schedule of corticosteroids for treatment of GPA evolved from clinical experience rather than randomised clinical trials, but one trial evaluated a reduced-dose regimen.[42] The 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. BMJ: plasma exchange and glucocorticoid dosing for patients with ANCA-associated vasculitis: a clinical practice guideline Opens in new window

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]

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.

Severe (life- or organ-threatening) disease

Severe (life- or organ-threatening) disease is treated with a high-dose corticosteroid plus either cyclophosphamide or rituximab.[37][41] In this setting, the corticosteroid is frequently given intravenously (as methylprednisolone) for 3 to 5 days prior to the oral corticosteroid. 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 in combination with corticosteroids to induce remission in life- or organ- threatening vasculitis.[38][45] Avacopan may also be considered as an adjunctive treatment to substantially reduce exposure to corticosteroids.[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]

Cyclophosphamide may be administered as daily oral or pulse intravenous therapy. For the large majority of patients, remission can be achieved with a regimen that includes 3 to 4 months of daily oral cyclophosphamide. In general, the period of treatment with cyclophosphamide should not exceed 6 months.[48] 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 daily oral and pulse intravenous cyclophosphamide administration 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.

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

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]

Non-severe disease

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

As part of a strategy to reduce exposure to corticosteroids, avacopan can be considered for patients treated with rituximab.[38]

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).[54] 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]

There is no established role for anti-tumour necrosis factor therapy in the treatment of GPA. Evidence suggests that the addition of etanercept to standard therapy is not associated with any reduction in relapse rate or improvement in other clinical outcomes.[56]

Refractory disease

Patients who do not respond to an appropriate remission induction regimen should be carefully evaluated for other comorbidities, such as infection and malignancy. Disease refractory to remission induction therapy is rare.

Intravenous immunoglobulin (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]

Patients with severe disease who do not respond to cyclophosphamide should typically be switched to rituximab, and vice versa.[37] Cyclophosphamide or rituximab can be used for non-severe disease in patients who do not respond to methotrexate or mycophenolate.[37] Patients with refractory disease require assessment and management in a specialist centre and should be considered for enrolment in clinical trials.[38]

Remission maintenance

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 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. An expert consensus guideline summarises the key issues pertaining to use of rituximab for remission maintenance and identifies priorities for further research.[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 to 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.[38]

Patients continue on corticosteroids during remission maintenance, although a proportion of patients with well-controlled symptoms can be slowly tapered off the corticosteroids.[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.

Disease relapses

Patients who experience a relapse are given a further course of remission induction therapy. The regimens used follow the same general principles described above; 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] Therefore, patients with a severe GPA 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.

Subglottic stenosis

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.

Reconstructive surgery

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]

Debulking surgery

Debulking surgery may rarely be considered, 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] However, this should only be considered in conjunction with a centre of vasculitis expertise.

Importance of careful assessment of disease activity

Careful assessment of disease activity is a prerequisite for appropriate therapeutic decision-making, as there can be a number of potential pitfalls:

Many findings initially attributable to active disease may only partially resolve with effective treatment (e.g., radiographic lung nodules)
Many findings initially attributable to active disease may be difficult to distinguish from tissue damage or infection (e.g., nasal crusting and discharge)
Many findings initially attributable to active disease may worsen independently of disease activity (e.g., dysaesthesias in a location previously affected by sensory peripheral neuropathy)
Certain disease manifestations, such as orbital pseudo-tumour or subglottic stenosis, are often poorly responsive to systemic immunosuppressive therapy.

Therefore, clinical features such as these should not be used to justify unduly prolonged treatment with remission induction regimens, in the absence of more clear-cut findings of active disease.

Supportive care

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.

Fertility protection

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]

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