Guideline sources The following summarized guidelines for the evaluation and management of granulomatosis with polyangiitis (GPA) are prepared by our editorial team based on guidelines from the European League Against Rheumatism (EULAR 2023), the Vasculitis Foundation (VF/ACR 2021), the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2021), and the Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE initiative 2019). 1 2 3 4 Calculator ACR/EULAR diagnostic criteria f https://web.pathway.md/diseases/recviPIXECDYZifbb 1/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway Guidelines 1. Diagnostic investigations Antineutrophil cytoplasmic antibodies: obtain both proteinase 3-ANCA and myeloperoxidase- ANCA testing, with a high-quality antigen-specific assay as the primary method of testing, in patients with signs and/or symptoms raising suspicion of a diagnosis of ANCA-associated vasculitis. A Serum immunoglobulins: measure serum immunoglobulin concentrations before each course of rituximab to detect secondary immunodeficiency in patients with ANCA-associated vasculitis receiving rituximab. B 2. Diagnostic procedures Biopsy: perform biopsies to assist in establishing a new diagnosis of ANCA-associated vasculitis and for further evaluation of patients suspected of having relapsing vasculitis. B 3. Medical management General principles: As per EULAR 2023 guidelines: Offer multidisciplinary management in centers with, or with ready access to, expertise in vasculitis in patients with ANCA-associated vasculitis. B Offer the best care based on shared decision-making between the patient and the physician, taking efficacy, safety, and costs into account, in patients with ANCA-associated vasculitis. B As per KDIGO 2021 guidelines: Manage patients with ANCA-associated vasculitis at centers with experience in ANCA- associated vasculitis. B Do not delay immunosuppressive therapy while waiting for a kidney biopsy to be performed or reported in patients with a clinical presentation compatible with small-vessel vasculitis and positive or proteinase 3-ANCA and myeloperoxidase-ANCA serology, especially in patients rapidly deteriorating. D Induction of remission: As per EULAR 2023 guidelines, initiate a combination of corticosteroids and either rituximab or cyclophosphamide for induction of remission in patients with new-onset GPA with organ- threatening or life-threatening disease. A Show 3 more Landmark trials: ADVOCATE https://web.pathway.md/diseases/recviPIXECDYZifbb 2/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway In patients with ANCA-associated vasculitis, avacopan was noninferior to prednisone with respect to remission at week 26. David R W Jayne et al. N Engl J Med. 2021 Feb 18. As per KDIGO 2021 guidelines, initiate corticosteroids in combination with cyclophosphamide or rituximab as initial therapy in patients with new-onset ANCA-associated vasculitis. B As per ACR 2021 guidelines, consider initiating methotrexate over cyclophosphamide or rituximab in patients with active, non-severe GPA. C Show 8 more Maintenance of remission: As per EULAR 2023 guidelines: Initiate rituximab for maintenance of remission after induction of remission with either rituximab or cyclophosphamide in patients with GPA. Consider initiating azathioprine or methotrexate as alternatives. B Continue therapy to maintain remission for 24-48 months following induction of remission in patients with new-onset GPA. B Consider continuing therapy for a longer duration in patients with relapse or with an increased risk of relapse, balanced against patient preferences and risks of continuing immunosuppression. B As per KDIGO 2021 guidelines, initiate low-dose corticosteroids and either rituximab or azathioprine as maintenance therapy after induction of remission in patients with GPA. B Show 6 more As per ACR 2021 guidelines, consider initiating rituximab over methotrexate or azathioprine for remission maintenance in patients with severe GPA entered remission after treatment with cyclophosphamide or rituximab. C Show 6 more Anticoagulant therapy: insufficient evidence to recommend an optimal duration of anticoagulation in patients with GPA experiencing venous thrombotic events. I 4. Therapeutic procedures Plasma exchange: As per EULAR 2023 guidelines: Consider performing plasma exchange as part of therapy to induce remission in patients with GPA with a serum creatinine > 300 mcmol/L due to active glomerulonephritis. B Do not perform plasma exchange routinely for the treatment of alveolar hemorrhage in patients with GPA. D As per KDIGO 2021 guidelines: https://web.pathway.md/diseases/recviPIXECDYZifbb 3/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway Consider performing plasma exchange in patients with serum creatinine > 5.7 mg/dL (500 mmol/l) requiring dialysis or with rapidly increasing serum creatinine, and in patients with diffuse alveolar hemorrhage having hypoxemia. C Perform plasma exchange in patients with an overlap syndrome of ANCA-associated vasculitis and anti-GBM. B As per ACR 2021 guidelines: Consider avoiding routine plasma exchange in addition to remission induction therapy in patients with GPA and active glomerulonephritis. D Consider avoiding plasma exchange in addition to remission induction therapy in patients with active, severe GPA and alveolar hemorrhage. D Landmark trials: PEXIVAS (plasmapheresis) In patients with severe ANCA-associated vasculitis, plasma exchange was not superior to no plasma exchange with respect to the composite outcome of death from any cause or end- stage kidney disease. Michael Walsh et al. N Engl J Med. 2020 Feb 13. 5. Surgical interventions Kidney transplantation: As per KDIGO 2021 guidelines, delay kidney transplantation until patients are in complete clinical remission for 6 months. Do not delay transplantation because of the persistence of ANCA. B As per ACR 2021 guidelines, consider evaluating patients with GPA in remission and stage 5 CKD for renal transplantation. C 6. Specific circumstances Pediatric patients (diagnosis and classification): Recognize that there are no validated diagnostic criteria for GPA. B Recognize that there are two different classification criteria for GPA: ACR criteria EULAR/PRINTO/PReS endorsed Ankara 2008 criteria. B Use the Ankara 2008 criteria for the classification of GPA in pediatric patients. B Pediatric patients (ANCA testing): obtain ANCA for the diagnosis of ANCA-associated vasculitis. B Show 2 more https://web.pathway.md/diseases/recviPIXECDYZifbb 4/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway Pediatric patients (diagnostic imaging): consider obtaining sinus CT or MRI for the diagnosis of GPA. C Show 2 more Pediatric patients (biopsy): attempt histopathological confirmation of the diagnosis of ANCA- associated vasculitis while not delaying treatment in patients with organ- or life-threatening disease. B Show 2 more Pediatric patients (treatment): Consider initiating a biological agent in patients with ANCA-associated vasculitis with critical organ- or life-threatening disease failed standard vasculitis therapy or if concerns exist regarding cyclophosphamide toxicity. Administer B-cell depleting therapy as first-line therapy. C Add co-trimoxazole to help prevent bacterial infection, pneumocystis jiroveci pneumonia, and upper respiratory tract relapses in patients with GPA. B Patients with sinonasal involvement: Consider offering nasal rinses and topical nasal therapies (antibiotics, lubricants, and corticosteroids) in patients with sinonasal involvement in GPA. C Consider performing reconstructive surgery during remission, if desired by the patient, in patients with GPA having nasal septal defects and/or nasal bridge collapse. C Patients with renal involvement: insufficient evidence to support the use of rituximab and corticosteroids in patients presenting with markedly reduced or rapidly declining GFR (serum creatinine > 4 mg/dL; > 354 mmol/L). Prefer cyclophosphamide and corticosteroids for induction therapy, or a combination of rituximab and cyclophosphamide as an alternative. I Show 3 more Patients with respiratory tract involvement: As per KDIGO 2021 guidelines: Consider performing plasma exchange in patients with diffuse alveolar hemorrhage having hypoxemia. C Perform plasma exchange in patients with an overlap syndrome of ANCA-associated vasculitis and anti-GBM. B As per ACR 2021 guidelines, consider initiating immunosuppressive therapy over performing surgical dilation with intralesional corticosteroid injection alone in patients with GPA and actively inflamed subglottic and/or endobronchial tissue with stenosis. C Patients with mass lesions: consider initiating immunosuppressive therapy over performing surgical removal of the mass lesion with immunosuppressive therapy in patients with GPA and mass lesions (such as orbital pseudotumor or masses of the parotid glands, brain, or lungs). C 7. Patient education https://web.pathway.md/diseases/recviPIXECDYZifbb 5/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway General counseling: provide patients with ANCA-associated vasculitis education focusing on the impact of ANCA-associated vasculitis and its prognosis, key warning symptoms, and treatment (including treatment-related complications). B 8. Preventative measures Prophylaxis for Pneumocystis jirovecii pneumonia: Administer TMP-SMX for prophylaxis against P. jirovecii pneumonia and other infections in patients with ANCA-associated vasculitis receiving rituximab, cyclophosphamide, and/or high doses of corticosteroids. B As per ACR 2021 guidelines, consider administering prophylaxis for the prevention of P. jirovecii pneumonia in patients with GPA receiving rituximab or cyclophosphamide. C 9. Follow-up and surveillance Serial clinical assessment: Obtain periodic assessment for treatment-related adverse effects and comorbidities in patients with ANCA-associated vasculitis. Offer prophylaxis and lifestyle advice to reduce treatment- related complications and other comorbidities. B Obtain structured clinical assessment, rather than ANCA and/or CD19-positive B cell testing alone, to inform decisions on changes in treatment in patients with ANCA-associated vasculitis. B Serial laboratory assessment: do not use the persistence of ANCA positivity, an increase in ANCA levels, or a change in ANCA from negative to positive to guide treatment decisions, as those are only modestly predictive of future disease relapse. D Management of refractory disease: As per EULAR 2023 guidelines, obtain a thorough reassessment of disease status and comorbidities and consider offering additional or different treatment in patients with GPA refractory to therapy to induce remission. Manage patients with refractory disease in close conjunction with, or refer to, a center with expertise in vasculitis. B As per KDIGO 2021 guidelines: Consider increasing the dose of corticosteroids (IV or PO), or adding rituximab if cyclophosphamide induction had been used previously, or vice versa, in patients with refractory disease. Consider performing plasma exchange. C Consider performing plasma exchange, in addition to corticosteroids with either cyclophosphamide or rituximab, in patients with diffuse alveolar bleeding with hypoxemia. C As per ACR 2021 guidelines: Consider switching to other therapy over combining two therapies in patients with severe GPA refractory to rituximab or cyclophosphamide for remission induction. C https://web.pathway.md/diseases/recviPIXECDYZifbb 6/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway Consider administering IVIG in addition to current therapy in patients with GPA refractory to remission induction therapy. C Management of relapse: As per EULAR 2023 guidelines, initiate a combination of corticosteroids and either rituximab or cyclophosphamide, preferably rituximab, B for induction of remission in patients with relapsing GPA. A As per KDIGO 2021 guidelines, reintroduce corticosteroids in combination with cyclophosphamide or rituximab (preferably rituximab) in patients with relapsing disease (life- or organ-threatening). B As per ACR 2021 guidelines: Consider initiating rituximab over cyclophosphamide for remission re-induction in patients with GPA experienced relapse with severe disease manifestations and not receiving rituximab for remission maintenance. C Consider switching from rituximab to cyclophosphamide over administering additional rituximab for remission re-induction in patients with GPA experienced relapse with severe disease manifestations while receiving rituximab for remission maintenance. C Clinical findings Symptoms Past medical history Abdominal pain Cardiomyopathy Anorexia HF Anosmia Meningitis Arthralgia Raynaud's phenomenon Bloody sputum Recurrent sinusitis Blurred vision Neurological exam Cacosmia Cough Cranial nerve palsy Fever Peripheral neuropathy Headache Sensorineural hearing loss Hearing loss Head and neck exam Hematuria Hemoptysis Conductive hearing loss Limb numbness Nasal crusting Malaise Nasal septal deformation Myalgia Nasal septal perforation Nasal discharge Nasal ulcers Nasal obstruction Oral ulcers Nosebleed Orbital mass Otalgia Otorrhea Pleuritic chest pain Saddle nose deformity https://web.pathway.md/diseases/recviPIXECDYZifbb 7/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway Purulent sputum Respiratory exam Rhinitis Seizure Pleuritis Shortness of breath Stridor Vision loss Wheezing Weight loss Genitourinary exam Vital signs Macroscopic hematuria Hypertension Lab findings Ocular exam Urine RBC casts Conjunctivitis ESR Episcleritis serum CRP Retinal hemorrhage serum creatinine Scleritis urine protein Uveitis serum albumin Cardiac exam Serological findings Pericarditis c-ANCA p-ANCA Musculoskeletal exam Endoscopic findings Arthritis Subglottic stenosis Integument exam Blue toes Erythematous painful pinna Palpable purpura Skin nodules Skin ulceration Urticaria Hematological findings Anemia WBC count blood platelet count Imaging findings Cerebral mass Lung nodule Pleural effusion Pulmonary cavity Pulmonary infiltrates https://web.pathway.md/diseases/recviPIXECDYZifbb 8/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway Likelihood Ratios Pertinent positives The following findings increase the probability of granulomatosis with polyangiitis in adults. 4 Finding LR+ Value Positive c-ANCA 5.1 Positive p-ANCA 2.7 Pertinent negatives The following findings decrease the probability of granulomatosis with polyangiitis in adults. 4 Finding LR- Value Negative c-ANCA 0.4 Negative p-ANCA 0.8 Studies 2021 ADVOCATE In patients with ANCA-associated vasculitis, avacopan was noninferior to prednisone with respect to remission at week 26. David R W Jayne et al. N Engl J Med. 2021 Feb 18. 2020 PEXIVAS (corticosteroids) In patients with severe ANCA-associated vasculitis, a reduced-dose corticosteroid regimen was noninferior to a standard-dose corticosteroid regimen with respect to the composite outcome of death from any cause or end-stage kidney disease. Michael Walsh et al. N Engl J Med. 2020 Feb 13. Show 4 more References 1. Sharon A Chung, Carol A Langford, Mehrdad Maz et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2021 Aug;73 8 1366 1383. Open 2. Bernhard Hellmich, Beatriz Sanchez-Alamo, Jan H Schirmer et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis. 2023 Mar 16;ard-2022 223764. Open https://web.pathway.md/diseases/recviPIXECDYZifbb 9/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway 3. Nienke de Graeff, Noortje Groot, Paul Brogan et al. European consensus-based recommendations for the diagnosis and treatment of rare paediatric vasculitides - the SHARE initiative. Rheumatology Oxford). 2019 Apr 1;58 4 656 671. Open 4. Kidney Disease: Improving Global Outcomes KDIGO Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100 4S S1 S276. Open 5. Hagen EC, Daha MR, Hermans J et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney Int. 1998 Mar;53 3 743 53. Open 6. Seza Ozen, Angela Pistorio, Silvia M Iusan et al. EULAR/PRINTO/PRES criteria for Henoch-Sch nlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II Final classification criteria. Ann Rheum Dis. 2010 May;69 5 798 806. Open 7. Pamela M K Lutalo, David P D'Cruz. Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener's granulomatosis). J Autoimmun. Feb-Mar 2014;48 49 94 8. Open 8. Michael Walsh, Peter A Merkel, Chen-Au Peh et al. Plasma Exchange and Glucocorticoids in Severe ANCA Associated Vasculitis. N Engl J Med. 2020 Feb 13;382 7 622 631. Open 9. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 10. Joanna C Robson, Peter C Grayson, Cristina Ponte et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for granulomatosis with polyangiitis. Ann Rheum Dis. 2022 Mar;81 3 315 320. Open 11. Eleana Ntatsaki, David Carruthers, Kuntal Chakravarty et al. BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology Oxford). 2014 Dec;53 12 2306 9. Open https://web.pathway.md/diseases/recviPIXECDYZifbb 10/10