Diagnosis

Statement 1

ANCA testing with ELISA and indirect immunofluorescence methods should be performed for diagnostic purposes in patients in whom there is clinical suspicion of a systemic small- and/or medium-sized vessel vasculitis.

Statement 2

Tissue biopsy should be considered in cases of suspected AAV to confirm diagnosis.

Classification of disease severity in AAV

Statement 3

Patients with AAV should have the extent and severity of their disease categorized as ‘severe’ at the time of diagnosis and in case of subsequent relapse if they have life- or major organ-threatening manifestations in order to tailor therapy accordingly.

The role of referral centres for vasculitis

Statement 4

Patients with AAV, particularly those with challenging disease, should be managed at or in collaboration with, a referral centre for vasculitis.

Remission induction for newly-diagnosed disease

Remission induction in severe (organ/life-threatening disease) newly-diagnosed disease

Recommendation 1

We recommend remission induction therapy with a combination of high dose glucocorticoids and cyclophosphamide in patients with severe newly diagnosed GPA, MPA or EGPA.

1B/A

Recommendation 2

We recommend using high dose glucocorticoids with rituximab as 1st line remission induction therapy in patients with severe GPA or MPA in whom cyclophosphamide is contraindicated or in whom cyclophosphamide presents an unacceptable risk of infertility.

1B/A

Recommendation 3

Cyclophosphamide dose should be adjusted in patients >60 years of age and in those with renal impairment.

1B/B

Statement 5

Complete blood count (CBC) and serum creatinine level must be monitored in patients treated with cyclophosphamide. In patients with abnormal CBC results, temporary withholding of cyclophosphamide and subsequent dose adjustments may be necessary depending on the degree of leucopenia.

Recommendation 4

We recommend that the remission induction therapy with cyclophosphamide, combined with glucocorticoids, lasts a minimum of 3 to a maximum of 6 months. Once remission is achieved, cyclophosphamide should be stopped and switched to a different maintenance therapy.

1B/A

Recommendation 5

We recommend that glucocorticoids should be given in adults at an initial dose of 1 mg/kg/day prednisone-equivalent for remission induction purposes. This may be preceded by pulsed methylprednisolone (0.5–1 g/day for 1–3 days) in patients with life threatening disease and/or major organ involvement.

2A/B

Recommendation 6

Prophylaxis against Pneumocystis jiroveci infection should be given to patients receiving cyclophosphamide or rituximab. This prophylaxis consists, in the absence of allergy, of trimethoprim/sulfamethoxazole compounds (800/160 mg 1 tablet 3 times per week or 400/80 mg daily).

3/C

Recommendation 7

There is insufficient evidence to support a recommendation that plasma exchange be used as first line therapy in any AAV patients. Plasma exchange may be a reasonable adjuvant therapy for patients who clinically deteriorate due to active vasculitis despite ongoing remission induction therapy with high-dose glucocorticoids and cyclophosphamide or rituximab.

4/D

Remission induction for limited or non-severe (non organ- and non life-threatening), newly-diagnosed disease

Recommendation 8

In patients with limited and/or non-severe GPA, which is non-life threatening and without any major organ involvement, remission induction regime with methotrexate in combination with glucocorticoids can be used.

1B / A

Recommendation 9

Patients with non-severe EGPA or non-severe MPA without renal involvement can be treated with glucocorticoids alone for remission induction. At present, there is no consensus on the use of any immunosuppressant agents in combination with glucocorticoids in patients with EGPA or MPA that are non-severe (including those with mononeuritis multiplex).

2B/C

Remission maintenance therapy

Recommendation 10

In patients with severe AAV in remission after a combined cyclophosphamide-glucocorticoid-based induction treatment, maintenance therapy can be based on azathioprine or methotrexate, initially in combination with low-dose glucocorticoids. Leflunomide or mycophenolate may be alternative agents in patients not tolerating or with contra-indications to azathioprine and methotrexate.

1B/B

Recommendation 11

In patients with severe AAV in remission after a combined cyclophosphamide-glucocorticoid-based induction treatment, maintenance therapy with rituximab infusions is an alternative to azathioprine, especially for those patients with PR3-ANCA-positive GPA.

1B/A

Statement 6

To date there is no definitive evidence to guide decisions for maintenance therapy after remission induction with rituximab.

Statement 7

Low dose glucocorticoids should be part of the initial remission maintenance therapy after remission is achieved; there is not enough evidence yet to support further recommendation on the optimal duration of low dose glucocorticoids.

Recommendation 12

We recommend the use of azathioprine, methotrexate or their alternatives (as per Recommendation 10 and 11) for remission maintenance therapy to be continued for a minimum of 18 months after successful remission induction. There is not enough evidence yet to support further recommendation on the optimal duration of their use for maintenance.

3/C

Recommendation 13

The use of trimethoprim/sulfamethoxazole (800/160 mg twice daily) as remission maintenance therapy can be considered in GPA as an adjuvant to immunosuppressant or after the cessation of maintenance immunosuppressive treatment.

3/C

Recommendation 14

Topical therapies may be considered, in combination with the systemic therapy and in collaboration with ENT subspecialists, to alleviate the symptoms of upper airway and ENT disease.

3/C

Relapsing disease

Recommendation 15

We recommend remission induction of a major organ- or life-threatening relapse with either cyclophosphamide or rituximab in conjunction with high dose glucocorticoids. In patients who already received cyclophosphamide for initial remission induction or a previous disease flare, we recommend using rituximab for remission re-induction.

1B/A

Recommendation 16

There is insufficient evidence to support a recommendation that plasma exchange be used as first line therapy in all patients with relapsing AAV with severe renal (GFR <50 ml/min) or pulmonary hemorrhage. Plasma exchange may be a reasonable adjuvant therapy for patients who clinically deteriorate due to active relapsing vasculitis despite ongoing remission induction therapy with high-dose glucocorticoids and cyclophosphamide or rituximab.

4/D

Recommendation 17

We recommend that relapses that are non-severe, i.e. non-life and non-organ threatening, be treated with an increase in glucocorticoid dose in addition to optimizing the patient’s concurrent immunosuppressant agent.

3/C

Refractory disease

Recommendation 18

We recommend the use of rituximab, in combination with glucocorticoids, in patients with severe GPA or MPA who fail to respond to cyclophosphamide as remission induction therapy.

3/C

Statement 8

Patients with refractory disease should be managed in a referral centre for vasculitis in collaboration with subspecialists with experience in managing such patients.

Statement 9

Patients with EGPA and persistent asthmatic symptoms, despite remission of their vasculitic manifestations, should be managed in collaboration with a physician subspecializing in asthma management.

Additional and experimental therapies

Statement 10

In patients in whom the aforementioned therapies are ineffective, contraindicated or poorly tolerated, consideration can be given to alternate, additional and/or experimental therapies in collaboration with a referral centre for vasculitis.

Follow up of patients with AAV

Statement 11

Patients with AAV should be followed regularly for many years with full clinical assessment and routine laboratory work to assess disease course and track for disease activity and disease- or treatment-related damage.

Statement 12

All patients previously treated with cyclophosphamide should have a urinalysis every 3–6 months as a lifelong means of screening for cyclophosphamide-induced bladder toxicity. If micro- or macroscopic hematuria is present, in the absence of an alternate explanation, the patient should be referred for consideration of a cystoscopy.

Statement 13

As part of their lifelong annual follow-up, cardiovascular risk factors (including smoking status, diabetes, hypercholesterolemia, hypertension and obesity) and risk for osteoporosis should be systematically assessed, with treatment as needed according to the current respective guidelines for each of these conditions.

Special patient groups

Statement 14

Women with AAV should not consider pregnancy earlier than 6 months after sustained remission of their disease has been achieved. Women with AAV planning pregnancy and those pregnant should be managed in close collaboration with an obstetrician with expertise in this field and/or in high-risk pregnancies.

Statement 15

There are no pediatric specific management guidelines for pediatric AAV, and most knowledge in pediatric AAV is adapted from adult research. Management of children with AAV should be provided by pediatric physicians at an academic healthcare Centre, in collaboration with referral centres for vasculitis and/or centres with special interest in pediatric vasculitis.

Statement 16

AAV in children should be classified at the time of diagnosis based on the childhood EULAR/PRINTO/PReS criteria in order to tailor therapy accordingly.

Statement 17

Children with newly diagnosed AAV should be treated according to adult recommendations for induction of remission and then maintenance, with dose of medications adjusted for this specific population.

Recommendation 19

In children, severe relapsing AAV or severe AAV refractory to the combination of cyclophosphamide and glucocorticoids (with major organ involvement or life-threatening manifestations) should be treated with rituximab, in combination with glucocorticoids.

4/D