ACR/Vasculitis Foundation 2021 Guidelines for ANCA–Associated Vasculitis Save

Jack Cush, MD

Jul 14, 2021 5:55 pm

Chung et al have published the 2021 treatment guielines for the management of antineutrophil cytoplasmic antibody–associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). These guidelines are put forth by the American College of Rheumatology and the Vasculitis Foundation as benchmark guidance to assist health care professionals in managing AAV.

Guidelines were developed by a voting panel of using GRADE methodology and answering a series of PICO questions (47 for GPA/MPA, 34 for EGPA) based on a systematic literature review and expert consensus. Recommendation required ≥70% consensus among the Voting Panel. The Voting Panel included 9 adult rheumatologists, 5 pediatric rheumatologists, and 2 patients.

In the end the panel put forth 26 recommendations and 5 ungraded position statements for GPA/MPA; and 15 recommendations and 5 ungraded position statements for EGPA. Ungraded position statements reflect the lack of evidence for one intervention over the other, but since these are commonly encountered clinical questions, they labeled such guidance as “ungraded position statements". These are noted in italics below.

The guidelines include recommendations for the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. Notably they recommend against plasma exchange during induction therapy for GPA/MPA with alveolar hemorrhage or glomerulonephritis. Also in active nonsevere GPA/MPA they recommended methotrexate over RTX or CTX or steroids or other DMARDs (eg AZA). They do recommend dosing according to ANCA titers and B cell numbers. Lastly, GPA/MPA patients on RTX or CTX should receive prophylaxis to prevent Pneumocystis jirovecii pneumonia.

Most of the recommendations were conditional (expert opinion), as most of the PICO questions could not be fully answered (due to a lack of of multiple randomized controlled trials or low-quality evidence). Panel Recommendations are listed below.

Recommendations/statements for the Management of GPA and MPA

Remission induction for active, severe disease
1. Recommendation: For patients with active, severe GPA/MPA, we conditionally recommend treatment with rituximab over cyclophosphamide for remission induction
2. Recommendation: In patients with GPA/MPA with active glomerulonephritis, we conditionally recommend against the routine addition of plasma exchange to remission induction therapy
3. Recommendation: In patients with active, severe GPA/MPA with alveolar hemorrhage, we conditionally recommend against adding plasma exchange to remission induction therapies
4. Ungraded position statement: For patients with active, severe GPA/MPA, either IV pulse GCs or high-dose oral GCs may be prescribed as part of initial therapy
5. Recommendation: In patients with active, severe GPA/MPA, we conditionally recommend a reduced-dose GC regimen over a standard-dose GC regimen for remission induction
Remission induction for active, nonsevere disease
1. Recommendation: For patients with active, nonsevere GPA, we conditionally recommend initiating treatment with methotrexate over cyclophosphamide or rituximab.
2. Recommendation: For patients with active, nonsevere GPA, we conditionally recommend initiating treatment with methotrexate and GCs over GCs alone.
3. Recommendation: For patients with active, nonsevere GPA, we conditionally recommend initiating treatment with methotrexate and GCs over azathioprine and GCs or mycophenolate mofetil and GCs.
4. Recommendation: For patients with active, nonsevere GPA, we conditionally recommend initiating treatment with methotrexate and GCs over trimethoprim/sulfamethoxazole and GCs
Remission maintenance
1. Recommendation: For patients with severe GPA/MPA whose disease has entered remission after treatment with cyclophosphamide or rituximab, we conditionally recommend treatment with rituximab over methotrexate or azathioprine for remission maintenance
2. Recommendation: For patients with GPA/MPA who are receiving rituximab for remission maintenance, we conditionally recommend scheduled re-dosing over using ANCA titers or CD19+ B cell counts to guide re-dosing
3. Recommendation: For patients with severe GPA/MPA whose disease has entered remission after treatment with cyclophosphamide or rituximab, we conditionally recommend treatment with methotrexate or azathioprine over mycophenolate mofetil for remission maintenance.
4. Recommendation: For patients with severe GPA/MPA whose disease has entered remission after treatment with cyclophosphamide or rituximab, we conditionally recommend treatment with methotrexate or azathioprine over leflunomide for remission maintenance
5. Recommendation: For patients with GPA whose disease has entered remission, we conditionally recommend treatment with methotrexate or azathioprine over trimethoprim/sulfamethoxazole for remission maintenance
6. Recommendation: In patients with GPA whose disease has entered remission, we conditionally recommend against adding trimethoprim/sulfamethoxazole to other therapies (e.g., rituximab, azathioprine, methotrexate, etc.) for the purpose of remission maintenance
7. Recommendation: For patients with GPA/MPA receiving remission maintenance therapy with rituximab who have hypogammaglobulinemia (e.g., IgG <3 gm/liter) and recurrent severe infections, we conditionally recommend immunoglobulin supplementation
8. Ungraded position statement: The duration of non-GC remission maintenance therapy in GPA/MPA should be guided by the patient’s clinical condition, preferences, and values
9. Ungraded position statement: The duration of GC therapy for GPA/MPA should be guided by the patient’s clinical condition, preferences, and values
Treatment of disease relapse
1. Recommendation: For patients with GPA/MPA who have experienced relapse with severe disease manifestations and are not receiving rituximab for remission maintenance, we conditionally recommend treatment with rituximab over cyclophosphamide for remission re-induction
2. Recommendation: For patients with GPA/MPA who experienced relapse with severe disease manifestations while receiving rituximab for remission maintenance, we conditionally recommend switching from rituximab to cyclophosphamide over receiving additional rituximab for remission re-induction
Treatment of refractory disease
1. Recommendation: For patients with severe GPA/MPA that is refractory to treatment with rituximab or cyclophosphamide for remission induction, we conditionally recommend switching treatment to the other therapy over combining the 2 therapies
2. Recommendation: For patients with GPA/MPA that is refractory to remission induction therapy, we conditionally recommend adding IVIG to current therapy
Treatment of sinonasal, airway, and mass lesions
1. Ungraded position statement: For patients with sinonasal involvement in GPA, nasal rinses and topical nasal therapies (antibiotics, lubricants, and GCs) may be beneficial
2. Recommendation: For patients with GPA in remission who have nasal septal defects and/or nasal bridge collapse, we conditionally recommend reconstructive surgery, if desired by the patient
3. Recommendation: For patients with GPA and actively inflamed subglottic and/or endobronchial tissue with stenosis, we conditionally recommend treating with immunosuppressive therapy over surgical dilation with intralesional GC injection alone
4. Recommendation: For patients with GPA and mass lesions (e.g., orbital pseudotumor or masses of the parotid glands, brain, or lungs), we conditionally recommend treatment with immunosuppressive therapy over surgical removal of the mass lesion with immunosuppressive therapy
Other considerations
1. Recommendation: In patients with GPA/MPA, we conditionally recommend against dosing immunosuppressive therapy based on ANCA titer results alone
2. Recommendation: For patients with GPA who are receiving rituximab or cyclophosphamide, we conditionally recommend prophylaxis to prevent Pneumocystis jirovecii pneumonia
3. Recommendation: For patients with GPA/MPA in remission and stage 5 chronic kidney disease, we conditionally recommend evaluation for renal transplantation
4. Recommendation: For patients with active GPA/MPA who are unable to receive other immunomodulatory therapy, we conditionally recommend administering IVIG
5. Ungraded position statement: The optimal duration of anticoagulation is unknown for patients with GPA/MPA who experience venous thrombotic events

Recommendations/statements for the management of EGPA

Remission induction for active, severe disease
1. Ungraded position statement: For patients with active, severe EGPA, either IV pulse GCs or high-dose oral GCs may be prescribed as initial therapy
2. Ungraded position statement: For patients with active, severe EGPA, either cyclophosphamide or rituximab may be prescribed for remission induction
3. Recommendation: For patients with active, severe EGPA, we conditionally recommend treatment with cyclophosphamide or rituximab over mepolizumab for remission induction
Remission induction for active, nonsevere disease
1. Recommendation: For patients with active, nonsevere EGPA, we conditionally recommend initiating treatment with mepolizumab and GCs over methotrexate, azathioprine, or mycophenolate mofetil and GCs
2. Recommendation: For patients with active, nonsevere EGPA, we conditionally recommend initiating treatment with methotrexate, azathioprine, or mycophenolate mofetil and GCs over GCs alone
3. Recommendation: For patients with active, nonsevere EGPA, we conditionally recommend initiating treatment with methotrexate, azathioprine, or mycophenolate mofetil and GCs over cyclophosphamide or rituximab and GCs
Remission maintenance
1. Recommendation: For patients with severe EGPA whose disease has entered remission with cyclophosphamide therapy, we conditionally recommend treatment with methotrexate, azathioprine, or mycophenolate mofetil over rituximab for remission maintenance
2. Recommendation: For patients with severe EGPA whose disease has entered remission, we conditionally recommend treatment with methotrexate, azathioprine, or mycophenolate mofetil over mepolizumab for remission maintenance
3. Ungraded position statement: The duration of GC therapy in EGPA should be guided by the patient’s clinical condition, values, and preferences
Treatment of relapse
1. Recommendation: For patients with EGPA who have experienced relapse with severe disease manifestations after prior successful remission induction with cyclophosphamide, we conditionally recommend treatment with rituximab over cyclophosphamide for remission re-induction
2. Recommendation: For patients with EGPA who have experienced relapse with severe disease manifestations after prior successful remission induction with rituximab, we conditionally recommend treatment with rituximab over switching to cyclophosphamide for remission re-induction
3. Recommendation: For patients with EGPA who have experienced relapse with nonsevere disease manifestations (asthma and/or sinonasal disease) while receiving methotrexate, azathioprine, or mycophenolate mofetil, we conditionally recommend adding mepolizumab over switching to another agent
4. Recommendation: For patients with EGPA who have experienced relapse with nonsevere disease manifestations (asthma and/or sinonasal disease) while receiving low-dose GCs and no other therapy, we conditionally recommend adding mepolizumab over adding methotrexate, azathioprine, or mycophenolate mofetil
5. Recommendation: For patients with EGPA and high serum IgE levels who have experienced relapse with nonsevere disease manifestations (asthma and/or sinonasal disease) while receiving methotrexate, azathioprine, or mycophenolate mofetil, we conditionally recommend adding mepolizumab over adding omalizumab
Other considerations
1. Recommendation: For patients with newly diagnosed EGPA receiving leukotriene inhibitors, we conditionally recommend continuing leukotriene inhibitors over discontinuing them
2. Ungraded position statement: Use of leukotriene inhibitors is not contraindicated for patients with EGPA with active asthma and/or sinonasal disease
3. Recommendation: For patients with EGPA, we conditionally recommend obtaining an echocardiogram at the time of diagnosis
4. Recommendation: For patients with EGPA, we conditionally recommend using the Five-Factor Score to guide therapy
5. Ungraded position statement: In patients with sinonasal involvement in EGPA, treatment with nasal rinses and topical therapies (e.g., antibiotics, lubricants, and GCs) may be considered
6. Recommendation: For patients with EGPA who are receiving cyclophosphamide or rituximab, we conditionally recommend prescribing medications for prophylaxis to prevent Pneumocystis jirovecii pneumonia.