CanVasc Recommendations for the Management of Antineutrophil Cytoplasm Antibody-associated Vasculitides

1. Diagnosis

Statement 1. ANCA testing with ELISA and indirect immunofluorescence (IIF) 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.

The AAV are systemic vasculitides that predominantly affect small vessels and can manifest in a wide variety of ways depending on the target organ(s) involved and the severity of the disease. There are currently no validated diagnostic criteria for AAV and no precise or specific diagnostic tests. The ACR criteria^14,15,27 and the Chapel Hill Consensus Conference^1,2 definitions are useful tools in the assessment of a patient with vasculitis, possibly AAV, but it is important to remember that these are classification criteria and nomenclature definitions, respectively, for use in clinical trials and teaching. A study to develop diagnostic and classification criteria for systemic vasculitis is ongoing²⁸.

AAV are often, but not invariably, associated with the presence of circulating ANCA: 60% to 90% of cases of GPA and MPA are ANCA-positive. A cytoplasmic labeling pattern (cANCA) on immunofluorescence and anti-proteinase 3 (PR3) specificity on ELISA are more common in GPA, whereas perinuclear labeling pattern on immunofluorescence (pANCA) and anti-myeloperoxidase (MPO) specificity on ELISA are more common in MPA. Only 30% to 40% of cases of EGPA are ANCA-positive, mostly pANCA with anti-MPO specificity.

In the appropriate clinical setting, ANCA testing can be extremely useful in the diagnosis of AAV and should be performed by IIF, and samples positive for ANCA by IIF should be tested for PR3 and MPO by ELISA^2,29,30. The sensitivities and specificities of positive tests for cANCA targeted against PR3 or pANCA targeted against MPO are high. The combination of IIF and ELISA for ANCA testing at diagnosis can be helpful to identify discordant results. For example, a positive pANCA by IIF with PR3-ANCA on ELISA can occur in cocaine-levamisole–induced vasculopathy. A positive ANCA by IIF with ELISA results other than PR3-ANCA or MPO-ANCA in ELISA may also be observed with other conditions, such as inflammatory bowel diseases, cystic fibrosis, or infections^31,32,33,34. In the future, other ANCA screening techniques may be used in combination or instead of IIF and conventional ELISA, including automated image analysis of immunofluorescence patterns, “third-generation PR3-ANCA and MPO-ANCA ELISA,” and multiplex technology³⁵.

Barriers to implementation: A diagnosis of AAV cannot be excluded on the basis of a negative ANCA test. Some Canadian centers may not have easy access to both IIF and ELISA.

Previous guidance: 2014 BSR²¹, CARI^9,11, EULAR/EUVAS⁶

Statement 2. Tissue biopsy should be considered in cases of suspected AAV to confirm diagnosis.

We recommend obtaining a tissue biopsy to confirm the diagnosis and rule out vasculitis mimickers in all patients with suspected AAV, when feasible. Tissue biopsy is particularly important in patients who are ANCA-negative or in whom there is a degree of diagnostic uncertainty. Importantly, tissue biopsy should not delay treatment in obvious cases or life-threatening situations. The proportion of patients with AAV and a “positive” biopsy who demonstrate features of granuloma, vasculitis, or both has been quoted at about 70%³⁶, but the diagnostic yield varies greatly depending on the organ biopsied (Online Appendix 1, available at jrheum.org). It is important to recognize that a negative or “nondiagnostic” biopsy does not exclude a diagnosis of AAV. This is particularly true of ENT biopsies, for which sensitivity is below 53%³⁷. Biopsy can occasionally guide therapeutic decisions and provide valuable prognostic information. For example, a biopsy can help distinguish active renal vasculitis from renal damage in patients with deteriorating renal function and a prior history of renal involvement. However, kidney biopsy goals should be outlined before the biopsy.

Barriers to implementation: Limitations in the timely access to biopsy and biopsy results.

Previous guidance: EULAR/EUVAS⁶

2. 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, to allow therapy to be tailored accordingly.

The AAV are a heterogeneous group of disorders and the clinical course can be extremely varied. Therapy should be tailored according to disease extent and severity, and we therefore propose that patients with AAV be classified according to disease severity because this will affect therapeutic indications and contraindications.

For the purpose of these Canadian recommendations, the working committee defines severe AAV by the presence of life- or major organ-threatening manifestations, including severe and progressive kidney involvement; severe alveolar hemorrhage; severe gastrointestinal, cardiac, central nervous system (CNS), and/or eye involvement(s); or any other manifestations considered severe enough to require induction treatment with cyclophosphamide (CYC) or RTX. Importantly, the recommendation working committee recognizes that these definitions are wide-ranging and not constrained.

The use of existing tools may help to classify disease severity, but should not be restrictive because there are situations in which it remains difficult to readily classify disease severity. Two tools have been previously used for classifying GPA disease extent and severity in trials: the classification into “limited” or “severe” used by the Wegener’s Granulomatosis Etanercept Trial (WGET) research group^36,38, and that adopted by the EUVAS group with localized, early systemic, generalized, severe, and refractory diseases (Online Appendix 2, available at jrheum.org)³⁹. These 2 classifications have many similarities and there are currently no data to demonstrate that either classification system is superior to the other, although the binomial WGET classification appears to the recommendation working committee to be simpler to use.

In the Rituximab for ANCA-associated Vasculitis (RAVE) trial⁴⁰, patients with GPA and MPA were categorized according to the Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG), with severe disease being defined as the presence of 1 or more of the major BVAS/WG items or disease severe enough to require treatment with CYC. The original (1996 version) 5-factor score (FFS) is a prognostic scoring system that was developed by the FVSG and uses 5 distinct disease features that have been proven in uni- and multivariate analyses to be valuable prognostic markers in EGPA and PAN⁴¹, and has been further validated in MPA⁴². These 5 prognostic factors include vasculitis-related cardiomyopathy, CNS involvement, severe gastrointestinal tract symptoms, renal insufficiency (creatinine > 1.58 mg/dl or 140 μmol/l), and proteinuria (> 1 g/day). An FFS = 1 was associated with a 25.9% 5-year mortality and a FFS ≥ 2 (2 or more factors present) was associated with a 45.9% 5-year mortality rate (Online Appendix 2, available at jrheum.org). The 2009-revised FFS has yet to be validated and therefore cannot be used similarly to score disease severity in EGPA to guide therapy (Online Appendix 2, available at jrheum.org)⁴³.

Finally, it is important for treating physicians to regularly assess disease severity because a patient’s disease characteristics may change from their baseline presentation and therapy may have to be adjusted accordingly.

Barriers to implementation: None.

Previous guidance: BSR⁸, 2014 BSR²¹, EULAR/EUVAS⁶

3. The role of referral centers for vasculitis

Statement 4. Patients with AAV, particularly those with challenging disease, should be managed at or in collaboration with a referral center for vasculitis.

The AAV are a heterogeneous and rare group of disorders and it can be difficult for general internists, rheumatologists, nephrologists, and other subspecialists to maintain expertise in their management. We therefore recommend that patients with vasculitis be managed in collaboration with a referral center for vasculitis when possible (see Online Appendix 8 for list and location of all CanVasc centers, available at jrheum.org). Patients presenting with unusual manifestations of AAV and those with refractory disease may especially benefit from the direct input of a referral center for vasculitis, where there may be better access to subspecialists as well as access to clinical studies and trials. There is a continuous need for such studies on these diseases. As an integral part of this document, 2 areas of uncertainty in which observational, mechanistic, and/or therapeutic randomized controlled trials (RCT) would significantly inform clinical practice and increase knowledge are described in the following section.

Barriers to implementation: There is a shortage of healthcare providers trained in the assessment and management of patients with AAV in Canada. The creation of CanVasc and the identification of CanVasc centers and collaborators across Canada (Online Appendix 8, available at jrheum.org) aimed to decrease the lag between identification and referral of patients with AAV.

Previous guidance: BSR⁸, 2014 BSR²¹, EULAR/EUVAS⁶

4. Remission induction for newly diagnosed disease

5. Remission maintenance therapy

Remission is defined by EULAR/EUVAS as the complete absence of clinical disease activity, including vasculitis and granulomatous manifestations whether receiving immunosuppressive therapy or not³⁹ (Appendix 1).

Recommendation 10. In patients with severe AAV in remission after a combined CYC-GC–based induction treatment, maintenance therapy can be based on AZA or MTX, initially in combination with low-dose GC. Leflunomide (LEF) or MMF may be alternative agents in patients not tolerating or with contraindications to AZA and MTX.

Longterm toxicity makes CYC an unattractive option for maintenance of remission after successful remission induction in AAV. Following remission induction therapy with CYC, the CYCAZAREM trial (cyclophosphamide vs azathioprine for early remission phase of vasculitis) found that AZA (2 mg/kg/day) was as effective as continuous CYC at maintaining remission and was associated with fewer side effects⁵⁴. MTX (20–25 mg/week) was proven to be of comparable efficacy to AZA after remission induction with CYC^55,80. MTX should be used with caution in patients with renal impairment. The use of LEF in maintaining remission is less well studied, but results of 1 prematurely ended randomized study indicated that, at a dose of 30 mg/day, LEF was more effective than MTX at preventing relapse despite being associated with a higher rate of adverse events⁸¹. At present, in parallel with practice in RA, a dose of 20 mg/day can be used and is likely associated with a lower frequency of side effects⁸². MMF (2–3 g/day) has been studied in this setting, but has been found in 1 randomized controlled study to be less effective than AZA at maintaining remission and should therefore not be used as a first-line agent for maintenance⁵⁷.

Evidence 1B, Strength of recommendation B

Barriers to implementation: None.

Previous guidance: BSR⁸, 2014 BSR²¹, CARI^9,11, EULAR/EUVAS⁶, JCS¹⁰, KDIGO¹³

Recommendation 11. In patients with severe AAV in remission after a combined CYC-GC–based induction treatment, maintenance therapy with RTX infusions is an alternative to AZA, especially for those patients with PR3-ANCA–positive GPA.

Results of several retrospective studies on the preemptive use of RTX for maintenance following induction with RTX or CYC in combination with GC in patients with GPA or MPA have suggested that it is safe and effective^53,83,84,85. The results of these studies indicate that it may even be superior to AZA or MTX in preventing relapses^84,85. The results of the FVSG MAINRITSAN trial (Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis) showed that RTX 500 mg at remission, 2 weeks later, and then every 6 months up to Month 18, is superior to AZA in preventing relapses (relapse rates of 5.3% vs 29.3% at 28 mos postremission, respectively), with a comparable safety profile⁸⁶. Because the patients in the FVSG MAINRITSAN study were predominantly patients with PR3-ANCA–positive GPA, the findings could not be generalized to all patients with AAV. The role of RTX in patients with MPA or MPO-ANCA–positive GPA, or who are ANCA-negative, has to be further studied. The optimal duration, dose, and interval between each RTX infusion have to be further investigated. Whether the monitoring of CD19 B cell count, ANCA titer, or other biological variables may guide the need for RTX reinfusion is also under study (MAINRITSAN 2; ClinicalTrials.gov Identifier: NCT01731561)⁵³.

Evidence 1B, Strength of recommendation A

Barriers to implementation: RTX maintenance funding is not yet approved by Health Canada.

Previous guidance: 2014 BSR²¹, 2011 FVSG²⁰

Statement 6. To date, there is no definitive evidence to guide decisions for maintenance therapy after remission induction with RTX.

At least theoretically, 4 possible strategies for maintenance therapy after RTX induction exist: (1) patients, at least those with PR3-ANCA–positive GPA, may be retreated with RTX at regular intervals, similarly to what can be done after CYC-based induction therapy⁸⁷; (2) patients may be retreated with RTX in response to laboratory variables, i.e., repopulation of peripheral CD19 B cell counts or rising ANCA titers⁵³; (3) patients may be retreated with RTX (or another remission-inducing agent) only on the grounds of clinical relapse^88,89; and (4) patients may be maintained on conventional maintenance immunosuppressant drugs such as AZA, MTX, MMF, or LEF^83,90. It is not yet known which of these strategies is optimal. The RITAZAREM trial [rituximab (RTX) or azathioprine (AZA) for remission after RTX induction; ClinicalTrials.gov Identifier: NCT01697267; results expected in 2018] is comparing AZA versus RTX (1 g every 4 mos for 20 mos) for maintenance in patients with relapsing ANCA-associated GPA or MPA who achieve remission with RTX (4 × 375 mg/m²).

Barriers to implementation: RTX maintenance funding is not yet approved by Health Canada.

Previous guidance: Guerry, et al⁷, 2014 BSR²¹

Statement 7. Low-dose GC 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 GC.

GC should be gradually tapered to a dose of 5–10 mg/day within 3 to 6 months of achieving remission (see Online Appendix 3 for examples of GC regimens used in RCT, available at jrheum.org). No RCT have yet assessed the optimum duration of GC in remission maintenance. One large metaanalysis looked at previous AAV studies that incorporated GC into their treatment protocols. Relapse rates were higher in patients who discontinued GC within 12 months of achieving remission⁹¹. Results of another single-center study from Chapel Hill have indicated that longterm PRED treatment even at a low dose does not limit the risk of relapse, but can increase the risk of infections⁹². The VCRC TAPIR study [Vasculitis Clinical Research Consortium — The Assessment of Prednisone In Remission Trial; ClinicalTrials.gov Identifier: NCT01940094] aims at evaluating the effects of continuing low-dose PRED as compared with stopping PRED treatment entirely in patients with GPA in remission after a disease flare that occurred within the past 12 months (results expected in late 2016).

Barriers to implementation: None.

Previous guidance: 2014 BSR²¹, EULAR/EUVAS⁶

Recommendation 12. We recommend the use of AZA, MTX, or their alternatives (as per Recommendations 10 and 11) for remission maintenance therapy to be continued for a minimum of 18 months after successful remission induction. There is not yet enough evidence to support further recommendation on the optimal duration of their use for maintenance.

To date, the optimum duration of maintenance immunosuppressant therapy is not known. There are retrospective studies suggesting that relapse rates are lower in patients continuing on maintenance therapy beyond 36 months⁹³. The REMAIN study (REmission MAINtenance therapy in AAV) is a EUVAS RCT that has randomized patients, after successful remission induction therapy, to receive 24 months of low-dose GC and AZA or 48 months low-dose GC and AZA (results expected in 2015). In the future, there may be data to support tailoring the duration of maintenance therapy according to clinical and biological predictors of relapse, such as the presence of PR3 versus MPO ANCA, but at present, work is ongoing in this field and no firm conclusions have been reached that can affect practice^94,95,96. Until these results are available, we recommend that maintenance therapy be continued for at least 18 months after successful remission induction, then subsequently discontinued or not at the physician’s discretion and according to the individual patient’s characteristics, treatment tolerance, and understanding of their subsequent risk of relapse.

Evidence 3, Strength of recommendation C

Barriers to implementation: None.

Previous guidance: BSR⁸, 2014 BSR²¹, EULAR/EUVAS⁶, KDIGO¹³, 2011 FVSG²⁰

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.

The use of full-dose trimethoprim/sulfamethoxazole (800/160 mg twice daily) as remission maintenance monotherapy has been associated with a higher overall relapse rate than that observed with conventional remission maintenance agents^97,98. Full-dose trimethoprim/sulfamethoxazole has demonstrated efficacy at preventing upper airway/ENT disease relapse^76,99, but has no proven benefit at reducing any other form of disease relapse. It should only be used as an adjunct agent or after completion of the maintenance immunosuppressive therapy. It should not be used as remission maintenance monotherapy. Because of important drug interactions, it should not be used at this high dose in conjunction with MTX, but is safe as an adjunct with AZA and LEF.

Evidence 3, Strength of recommendation C

Barriers to implementation: None.

Previous guidance: BSR⁸, CARI^9,11, EULAR/EUVAS⁶, KDIGO¹³

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.

The consequences of upper airway and ENT disease often continue to manifest (as damage) despite achieving successful disease remission. It should be noted that such persistent upper airway symptoms, such as nasal crusting or congestion, and symptoms due to stenosis of nasal passage or upper airway are thus not always attributable to active granulomatous disease and therefore do not necessarily require additional immunosuppressant therapy. Therapies aimed at managing these symptoms are often essential for patient well-being. Nasal and sinus rinses with saline may be helpful. Topical antibiotic creams and ointments, such as mupirocin or fusidic acid, can also be considered, but are usually of limited benefit. There are no clinical trial data to support their use for patients with symptomatic nasal crusting and ulcers, including those with chronic nasal carriage of Staphylococcus aureus. These local therapies have not been shown to lower the risk of relapse or progression from a limited ENT to a more systemic form of the disease in patients with GPA.

Evidence 3, Strength of recommendation C

Barriers to implementation: There is a shortage of ENT subspecialists trained in the assessment and management of patients with AAV in Canada.

Previous guidance: BSR⁸, 2014 BSR²¹, EULAR/EUVAS⁶

6. Relapsing disease

Relapsing disease is defined by EULAR/EUVAS as the reoccurrence or new onset of disease activity attributable to active vasculitis-related inflammation (Appendix 1)³⁹. It is useful to define the severity of disease at the time of relapse to guide treatment decisions. It must be recognized, however, that no classification criteria or scoring systems (including the FFS or BVAS) have been validated in the context of relapsing disease as opposed to newly diagnosed disease. In the context of clinical trials, EULAR/EUVAS suggest that relapses should be recorded as either minor or major. A major relapse is defined as the reoccurrence or new onset of potentially organ- or life-threatening disease activity that cannot be treated with an increase of GC alone and requires further escalation of treatment. All other relapses should be classified as minor. This classification strategy has not been validated, but may prove to be a useful tool in the setting of relapsing disease. In RAVE, severe GPA or MPA flares or relapses were defined as with a BVAS/WG score of 3 or more (≥ 3 minor items or 1 major item)⁴⁰.

Recommendation 15. We recommend remission induction of a major organ- or life-threatening relapse with either CYC or RTX in conjunction with high-dose GC. In patients who already received CYC for initial remission induction or a previous disease flare, we recommend using RTX for remission reinduction.

The RAVE study showed that RTX was more effective at Month 6 than CYC for remission induction in relapsing disease (67% vs 42% of relapsing patients achieved remission with RTX vs CYC, respectively)⁴⁰. At 18 months, without any maintenance therapy after RTX-based induction, this difference with the conventional staged CYC-AZA treatment persisted, though it was no longer a significant difference⁸⁸. We therefore recommend using RTX for remission reinduction in patients previously treated with CYC (irrespective of the cumulative dose previously received), those in whom CYC is contraindicated or in whom CYC was previously ineffective or not tolerated, and for patients wishing to preserve fertility (see Online Appendix 3 for RTX prescribing, available at jrheum.org). For the patients in whom RTX is contraindicated or who fail to respond to RTX, given at appropriate doses, retreatment with CYC can still be considered (in the absence of a clear contraindication, such as severe allergy). Such patients presenting with complex refractory disease may especially benefit from the direct input of a referral center for vasculitis (Statement 4).

Evidence 1B, Strength of recommendation A

Barriers to implementation: Current funding approval in Canadian provinces (Online Appendix 6, available at jrheum.org) for the use of RTX for remission induction is for patients with newly diagnosed or relapsing disease only in the context of a contraindication to CYC, including the previous administration of > 25 g of cumulative dose of CYC.

Previous guidance: BSR⁸, 2014 BSR²¹, EULAR/EUVAS⁶, 2011 FVSG²⁰, KDIGO¹³

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 because of active relapsing vasculitis despite ongoing remission induction therapy with high-dose GC and CYC or RTX.

See Recommendation 7 for more details on plasma exchange.

Evidence 4, Strength of recommendation D

Barriers to implementation: Limitations in access to centers at which plasma exchange treatment is available.

Previous guidance: BSR⁸, 2014 BSR²¹

Recommendation 17. We recommend that relapses that are nonsevere, i.e., nonlife– and nonorgan-threatening, be treated with an increase in GC dose in addition to optimizing the patient’s concurrent immunosuppressant agent.

The treatment of nonlife- and nonorgan-threatening disease relapses should include increasing the GC dose and optimizing the patient’s concurrent immunosuppressant agent. There is no evidence to suggest superiority of MTX over AZA, and data on LEF, MMF, abatacept, or RTX is very limited in this setting and mostly related to GPA^100,101. Further, it is not known whether patients with disease relapse after cessation of maintenance therapy should be treated with a more prolonged course of maintenance immunosuppressant therapy following their relapse. We therefore cannot make further or specific recommendations regarding the choice or change of immunosuppressant agent and the duration of therapy following a nonmajor disease relapse.

Evidence 3, Strength of recommendation C

Barriers to implementation: None.

Previous guidance: BSR⁸, 2014 BSR²¹, KDIGO¹³

7. Refractory disease

The term “refractory disease” applies to patients who fail to attain remission following “standard” induction therapy, which is tailored according to the severity and extent of disease. The precise timing of when disease should be labeled as refractory is less clear. EULAR/EUVAS propose that refractory disease is defined as (1) unchanged or increased disease activity after 4 weeks of appropriate-dose CYC with GC, (2) lack of response defined as ≤ 50% reduction in the Disease Activity Score and/or lack of improvement in at least 1 major item after 4–6 weeks of treatment, or (3) chronic persistent disease defined as the presence of at least 1 major or 3 minor items on the BVAS list despite 8 weeks of treatment³⁹. These EULAR/EUVAS definitions of refractory disease are complex and difficult to apply in everyday clinical practice. We therefore propose a simplified version: refractory disease being disease that is unchanged or worsened despite 6 weeks of appropriate remission induction therapy or the presence of persistent disease activity after 3 months of appropriate remission induction therapy.

Consideration should be given to the referral of patients with refractory disease to a center for vasculitis. In all cases of apparent refractory disease, it is imperative to reevaluate the patient to ensure the following: (1) the diagnosis is correct, (2) alternate infectious/neoplastic diagnoses have been excluded, and (3) the treatment, including choice of drug(s), dosage, and duration, was appropriate.

Having considered the above and confirmed a patient has refractory disease, the following recommendations should be taken into account for the ongoing management of this challenging patient group.

Recommendation 18. We recommend the use of RTX in combination with GC in patients with severe GPA or MPA who fail to respond to CYC as remission induction therapy.

The RITUXVAS⁵⁰ and RAVE⁴⁰ trials demonstrated that RTX is noninferior to CYC at inducing remission in patients with severe or life-threatening manifestations of AAV. Several retrospective series have reported the efficacy of RTX in patients with refractory disease^51,53. We recommend that patients who have an inadequate response to either 6 infusions of an appropriate dose of IV CYC (Online Appendix 3, available at jrheum.org) or 3 months of oral CYC be treated with RTX (see Online Appendix 3 for RTX prescribing advice, available at jrheum.org).

Evidence 3, Strength of recommendation C

Barriers to implementation: RTX is approved in Canada for these patients, but access may be limited by the delay in obtaining timely approval for the drug coverage, which can vary according to the province.

Previous guidance: BSR⁸, 2014 BSR²¹, EULAR/EUVAS⁶, 2011 FVSG²⁰, Guerry, et al⁷, KDIGO¹³

Statement 8. Patients with refractory disease should be managed in a referral center for vasculitis in collaboration with subspecialists with experience in managing such patients.

Because of the rarity of these diseases, it can be difficult for all physicians to achieve and maintain skills in managing patients with refractory disease. We therefore suggest that these patients be referred to a center for vasculitis. These patients usually also require the input of different sub-specialists who work regularly in close collaboration with referral centers for vasculitis. Granulomatous head and neck manifestations of GPA, such as subglottic stenosis and retro-orbital pseudo tumors, are examples of disease manifestations that are frequently resistant to systemic treatments and may require other specific treatments to improve symptoms and quality of life^{102,103,104,105,106}.

Barriers to implementation: There is a shortage of healthcare providers trained in the assessment and management of patients with AAV in Canada. The creation of CanVasc and the identification of CanVasc centers and collaborators across Canada (Online Appendix 8, available at jrheum.org) aimed to decrease the lag between identification and referral of patients with AAV.

Previous guidance: 2014 BSR²¹

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.

Patients with a diagnosis of EGPA may have resurgence of their asthma symptoms while taking maintenance immunosuppressant therapies or after discontinuing such therapies¹⁰⁷. If the vasculitic manifestations of the disease are in remission, we do not recommend that worsening asthmatic symptoms be regarded as refractory disease. Although the escalation or reintroduction of immunosuppressant therapy is not necessarily warranted, it (including AZA, MTX, LEF, or MMF) may be considered as a way to avoid taking or limit the use of GC. There is very little evidence looking at the optimal management of these patients. Followup with an asthma specialist to ensure adherence with asthma management guidelines should be systematically considered. Referral of patients to a referral center for vasculitis for further assessment should also be considered because therapeutic trials may exist for these patients.

Barriers to implementation: There is a shortage of physicians subspecializing in asthma management and trained in the assessment and management of patients with AAV in Canada. The creation of CanVasc and the identification of CanVasc centers and collaborators across Canada (Online Appendix 8, available at jrheum.org) aimed to decrease the lag between identification and referral of patients with AAV.

Previous guidance: No specific guidelines.

8. 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 center for vasculitis.

IV immunoglobulin (IVIG). A few series and open-label studies suggested that IVIG can help achieve remission, in combination with GC, in patients with refractory disease (in addition to immunosuppressants) and/or in those with contraindication to immunosuppressants^108,109. There has been only 1 RCT studying the use of IVIG therapy in AAV. Patients with active AAV despite immunosuppressant therapy were randomized to receive IVIG or placebo in addition to “standard” therapy: 82% versus 35% of patients demonstrated a 50% reduction in disease activity in the IVIG versus placebo groups, respectively¹¹⁰. This difference was observed up to 3 months following therapy, but no differences were noted beyond this time. The benefit of IVIG does not appear to be sustained after the cessation of the infusions. On the basis of the limited evidence, IVIG (see Online Appendix 3 for IVIG prescribing advice, available at jrheum.org) is not a substitute for more conventional immunosuppressant therapies. IVIG could, however, be a useful therapy in certain patient subgroups: as an adjunct in those with refractory disease, in pregnant patients in whom alternate immunosuppressants are contraindicated, in patients with active vasculitis, and in those with a current severe infection or high recurrence rate of severe infections.

Evidence 3, Strength of recommendation C

Antitumor necrosis factor-α (anti-TNF-α) agents. The WGET studied 180 patients with GPA who received standard induction therapy with either CYC followed by maintenance with MTX or AZA (severe disease) or MTX for both induction and maintenance (limited disease), in combination with GC, and either etanercept (ETN) or placebo during induction and maintenance therapies³⁸. At 27 months, only 50% of patients achieved a sustained remission, and there was no difference in sustained remission rates between the ETN and placebo groups. Further, there was a significantly higher rate of occurrence of solid tumors in both groups compared with the general population and in the ETN group compared with the placebo group during the study period. However, the latter difference between study groups was no longer significantly different during poststudy closure followup¹¹¹. Data on other anti-TNF-α agents are limited with only retrospective and open-labeled studies, which showed possible efficacy in selected patients. One small controlled study¹¹² of infliximab (IFX) versus RTX for refractory GPA showed that RTX was superior at inducing and maintaining remission during longterm followup^113,114,115. We therefore recommend that ETN not be used in regular practice for the treatment of AAV. The use of other anti-TNF-α agents, such as IFX, should be limited to very specific cases of refractory disease when other alternative therapeutic options have failed or cannot be used, and they should not be given in combination with CYC.

Evidence 1B, Strength of recommendation A

Mepolizumab. A few series showed promising results for IV mepolizumab, a monoclonal antibody directed against interleukin 5 for patients with EGPA GC-dependent and/or refractory to other immunosuppressants^116,117. The MIRRA trial (Mepolizumab Treatment In Relapsing or Refractory EGPA; ClinicalTrials.gov Identifier: NCT02020889) aims at studying subcutaneous mepolizumab for patients with EGPA who cannot taper PRED below 7.5 mg/day without the reappearance of disease manifestation(s).

Evidence 3, Strength of recommendation D

Anti-CD52 therapy. Alemtuzumab is a humanized monoclonal antibody to CD52 with antilymphocyte activity and has been shown in a case series to induce remission in AAV, although relapses and adverse events are common; its use in GPA is considered experimental¹¹⁸ and there is no approval for this drug for vasculitis in Canada.

Evidence 3, Strength of recommendation D

Barriers to implementation: There is a shortage of healthcare providers trained in the assessment and management of patients with AAV in Canada. The creation of CanVasc and the identification of CanVasc centers and collaborators across Canada (Online Appendix 8, available at jrheum.org) aimed to decrease the lag between identification and referral of patients with AAV. Access to the aforementioned therapies is not possible in every province and none of them is approved by Health Canada for AAV (access is restricted, with provincial formularies and/or the need to apply for provincial exceptional access program approval).

Previous guidance: BSR⁸, Cochrane Review of IVIG²³, EULAR/EUVAS⁶, KDIGO¹³

9. Followup 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.

Patients receiving remission induction and maintenance therapy require regular clinical assessment to monitor their disease course, response to treatment, and the potential adverse effects of treatments. The frequency at which this is done depends on the individual patient, the characteristics and history of their disease, and the therapies required. We suggest that patients receiving remission induction therapy be seen on a monthly basis and those receiving maintenance therapy be seen on a 3-monthly basis for the first 2 years. The frequency of subsequent followup visits could be tailored to the individual patient in continued and close collaboration with the patient’s family physician and other subspecialists possibly involved. Given that relapses of AAV can occur at any stage, we recommend that all patients be reviewed longterm, at least annually, to monitor for signs of relapse, to assess for potential longterm toxicities of immunosuppressant therapies, and in some cases to manage the repercussions of vasculitis-induced damage. At each visit, irrespective of the disease state, we recommend patients undergo a full clinical assessment and routine laboratory work (see Online Appendix 1 for suggested blood tests at followup, available at jrheum.org).

There is currently no evidence to suggest that rising ANCA titers alone warrant therapeutic changes, and therefore the need for serial ANCA testing is debatable^119,120,121. The value of monitoring CD19 B cell count in patients treated with RTX also remains to be determined because currently available data do not support that it is sensitive or specific enough to help predict relapses.

Barriers to implementation: There is a shortage of healthcare providers trained in the assessment and management of patients with AAV in Canada. The creation of CanVasc and the identification of CanVasc centers and collaborators across Canada (Online Appendix 8, available at jrheum.org) aimed to decrease the lag between identification and referral of patients with AAV.

Previous guidance: BSR⁸, 2014 BSR²¹, KDIGO¹³

Statement 12. All patients previously treated with CYC should have a urinalysis every 3–6 months as a lifelong means of screening for CYC-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.

It is widely recognized that the use of CYC is associated with bladder toxicity, namely hemorrhagic cystitis and bladder cancer^49,122,123. The risks have lessened somewhat over recent years, perhaps because of the more frequent coprescription of mesna (at least for hemorrhagic cystitis) and the lower cumulative doses of CYC used in patients with AAV. Nevertheless, we suggest that all patients previously treated with CYC, especially those who received high total cumulative doses of CYC, have urine dipstick testing at least every 3–6 months as part of their regular followup (cumulative doses given to patients in whom bladder cancer developed varied widely, above 30 gm in almost all cases and above 100 gm in the majority of them). If hematuria is present, the quantification of hematuria and urine cytopathology may be helpful. In the absence of an alternate explanation, such as infection, active renal disease, or renal damage of AAV, screening cystoscopy may be indicated and the patient should be referred for cystoscopy.

Barriers to implementation: None.

Previous guidance: BSR⁸, 2014 BSR²¹

Statement 13. As part of their lifelong annual followup, cardiovascular (CV) risk factors [including smoking status, diabetes, hypercholesterolemia, hypertension (HTN), 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.

There is good evidence that chronic inflammatory disorders such as RA or systemic lupus erythematosus are associated with an increased risk of longterm CV events^124,125. Publications in GPA and MPA describe a rate of CV events around 10% over a median 4.3-year followup period^48,126. The longterm use of GC increases the risk of osteoporosis. The presence of renal impairment in patients with AAV adds a level of complexity in the therapeutic decisions for the prevention of osteoporosis.

As part of their longterm annual followup, patients with AAV should thus also be assessed, in collaboration with their primary care provider and/or subspecialist comanaging them, for osteoporosis and CV risk factors, including smoking status, diabetes, hypercholesterolemia, HTN, and obesity, and be appropriately counseled and treated, irrespective of the state of their vasculitis. There is not enough evidence at present to recommend a standardized list of investigations to perform in all patients or an optimal frequency, other than annual CV (risk) assessment. The prevention of osteoporosis should rely on the last updated and available Canadian guidelines (available at www.osteoporosis.ca)^127,128,129.

Barriers to implementation: Collaborations with patient’s family physician and other healthcare providers specialized in the prevention and management of CV risk factors or osteoporosis must be encouraged to optimize this mandatory longterm followup.

Previous guidance: BSR⁸, 2014 BSR²¹, EULAR/EUVAS⁶

10. 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.

In the past, the high morbidity associated with AAV and the toxic feature of the available treatments meant that pregnancy was unusual in this patient group. Thus, there are limited data available on pregnancy, its management, and outcomes in women with AAV. Retrospective reports suggest that while significant worsening of the patient’s vasculitis is unusual during pregnancy, there are reports of pregnancy complications related to previous vasculitis-induced damage, such as cardiac decompensation, or problems related to chronic impairment of renal function. There may also be a higher rate of first trimester miscarriage, preterm labor, and the need for Cesarean section deliveries in these patients^130,131,132. Therefore, we suggest that these patients be seen before conception and monitored closely throughout pregnancy in close collaboration with the obstetric team. Published case series suggest that worsening vasculitis is less likely to occur in patients in sustained remission at the time of conception. Patients should therefore probably wait for at least 6 months after achieving sustained remission before attempting to conceive^{130,131,133,134}, and those stable on maintenance immunosuppression should be receiving pregnancy-safe options (i.e., AZA but not MTX, MMF, LEF, or any other teratogenic drugs). In view of the known teratogenicity of some of the drugs used in the management of AAV, including CYC, MTX, LEF, and MMF, it is imperative to advise patients to take appropriate contraceptive measures when treated with those immunosuppressants.

Barriers to implementation: There is a shortage of physicians subspecializing in high-risk pregnancies and trained in the assessment and management of patients with AAV in Canada. The creation of CanVasc and the identification of CanVasc centers and collaborators across Canada (Online Appendix 8, available at jrheum.org) aimed to decrease the lag between identification and referral of patients with AAV.

Previous guidance: None specifically.

Statement 15. There are no pediatric-specific management guidelines for pediatric AAV yet, 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 center in collaboration with referral centers for vasculitis and/or centers with special interest in pediatric vasculitis.

Because of the rarity of pediatric AAV, there have been no studies from which to develop pediatric-specific guidelines, and most knowledge has been adapted from adult literature and experience. For the same reason, few pediatricians have experience in diagnosing and managing children with AAV. Notwithstanding, children should be managed at a pediatric academic healthcare center by pediatric physicians who have an understanding of the potential effects of disease and treatments on growth and development. If necessary, there should be close collaboration with centers having a special interest in pediatric vasculitis. All patients should be invited to participate in national or international registries of childhood vasculitis with a view to improving pediatric-specific knowledge and care.

Barriers to implementation: There is a shortage of pediatric physicians subspecializing and/or trained in the assessment and management of patients with AAV in Canada. The creation of CanVasc and the identification of CanVasc centers and collaborators across Canada (Online Appendix 8, available at jrheum.org) aimed to decrease the lag between identification and referral of patients with AAV. Several pediatric referral centers for vasculitis are participating in the CanVasc research network.

Previous guidance: None.

Statement 16. AAV in children should be classified at the time of diagnosis based on the childhood EULAR/Paediatric Rheumatology International Trial Organization (PRINTO)/Paediatric Rheumatology European Society (PReS) criteria so that therapy can be tailored accordingly.

GPA is the most common of these rare childhood AAV, followed by MPA, and EGPA is extremely rare. A pediatric adaptation of the ACR criteria taking into account common pediatric manifestations and the presence of ANCA has enabled a specific classification for pediatric GPA, validated using a cohort of pediatric patients — EULAR/PRINTO/PReS criteria^135,136,137. Systematic use of pediatric classification and adopting adult systems for “disease severity classification” will provide a framework for tailoring therapy (see Statement 3) and will provide the cornerstone for subsequent development of pediatric-specific management guidelines.

Barriers to implementation: None.

Previous guidance: None.

Statement 17. Children with newly diagnosed AAV should be treated according to adult recommendations for induction of remission and then maintenance, with medication dose adjusted for this specific population.

Induction treatment for children with severe GPA or MPA should rely on a combination of high-dose GC plus either CYC or RTX. The dose of CYC must be adjusted in children with renal impairment and therapy should be monitored according to adult recommendations. Consideration should be given to RTX as first-line remission induction therapy in children with severe GPA or MPA in whom CYC is contraindicated or in whom CYC presents an unacceptable risk of infertility. An international open-label study is ongoing to assess the involvement of RTX in children with severe GPA or MPA (ClinicalTrials.gov Identifier: NCT01750697; results expected in mid-2017).

Plasma exchange should be considered in children with rapidly progressive, severe renal disease or severe pulmonary hemorrhage despite induction therapy with GC and CYC or RTX. In children with limited nonsevere disease, induction therapy regimen with MTX in combination with GC may be considered.

As in adults, prophylaxis against P. jirovecii infection should be given to children receiving CYC or RTX.

Remission induction therapy with CYC should be switched to maintenance treatment within 3–6 months. Maintenance treatment after remission induction through GC and CYC is based on adult recommendations of a combination of low-dose GC plus AZA or MTX for a minimum of 24 months. There is no evidence to guide decisions regarding the duration of GC therapy.

Barriers to implementation: In Canada, RTX is approved for induction therapy in adults with severe ANCA-positive GPA or MPA, but is not yet approved for children.

Previous guidance: None.

Recommendation 19. In children, severe relapsing AAV or severe AAV refractory to the combination of CYC and GC (with major organ involvement or life-threatening manifestations) should be treated with RTX in combination with GC.

Because AAV are relapsing conditions and a previous relapse is a risk factor for another and subsequent one⁹⁵, limiting the exposure to CYC in children is crucial. Children may experience multiple flares during their lifetime and repeated or sustained exposure to CYC can induce infertility, bladder cancer, or lymphoma^138,139. The use of RTX in combination with GC as first-line treatment for disease relapses should therefore be considered in children, especially if they have already received CYC, independent of their cumulative dose. However, it must be remembered that data on the longterm safety of RTX in children in AAV are lacking.

Evidence 4, Strength of recommendation D

Barriers to implementation: In Canada, RTX is approved for induction therapy in adults with severe ANCA-positive GPA or MPA, but is not yet approved for children.

Previous guidance: None.