Ntatsaki E, Carruthers D, Chakravarty K, et al; BSR and BHPR Standards, Guidelines and Audit Working Group. BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology (Oxford). 2014 Dec;53(12):2306-9. doi: 10.1093/rheumatology/ket445. Epub 2014 Apr 11. PubMed PMID: 24729399.
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013 Jan;65(1):1-11. doi: 10.1002/art.37715. PubMed PMID: 23045170.
Mukhtyar C, Guillevin L, Cid MC, et al; European Vasculitis Study Group. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. 2009 Mar;68(3):310-7. doi: 10.1136/ard.2008.088096. Epub 2008 Apr 15. PubMed PMID: 18413444.
Definition, Etiology, PathogenesisTop
Granulomatosis with polyangiitis (GPA), previously referred to as Wegener granulomatosis, is a granulomatous vasculitis that usually involves the upper and lower respiratory tracts, with associated necrotizing vasculitis affecting mainly small-sized and medium-sized vessels (ie, capillaries, venules, arterioles, arteries, and veins). GPA frequently leads to necrotizing glomerulonephritis, ocular vasculitis, pulmonary capillaritis with hemorrhage, and granulomatous and nongranulomatous extravascular inflammation.
GPA may also be limited to the upper or lower respiratory tract or to the eye. In these cases, features of systemic vasculitis may not be identified; however, in patients with clinical and histologic abnormalities identical to those seen in GPA, and particularly with a positive antineutrophil cytoplasmic antibody (ANCA) test result, the diagnosis of GPA should be made.
Clinical Features and Natural HistoryTop
Signs and symptoms:
1) Upper respiratory tract manifestations: Nasal congestion, mucosal ulcerations (may be painless), purulent and/or bloody nasal discharge or epistaxis, perforation of the nasal septum and destruction of the nasal cartilage resulting in a saddle nose deformity, symptoms of chronic sinusitis, hoarseness, features of upper airway obstruction caused by a developing subglottic stricture.
2) Otitis media, sometimes leading to hearing loss.
3) Pulmonary manifestations (present in ~90% of patients but asymptomatic in one-third): Cough and hemoptysis (may be severe in patients with diffuse alveolar hemorrhage), dyspnea, pleural pain.
4) Renal manifestations: Glomerulonephritis (in >70% of patients, frequently asymptomatic [abnormalities are observed mainly in the urinary sediment]; sometimes disease is limited to the kidneys). Concomitant involvement of the lungs and kidneys is known as pulmonary-renal syndrome.
5) Ocular manifestations: Episcleritis, scleritis, conjunctivitis, uveitis, dacryocystitis, rarely orbital pseudotumor with exophthalmos and diplopia, optic neuritis, ocular vasculitis (this may lead to irreversible loss of vision).
6) Skin manifestations (in 40%-60% of patients): Most frequently palpable purpura, less often ulcerating papules (particularly on the limbs) and subcutaneous nodules. Rarely necrosis.
7) Musculoskeletal manifestations: Myalgia and arthralgia. Less frequently other features of arthritis (occasionally symmetric but with no erosions or deformities).
8) Nervous system manifestations (in advanced disease): Most frequently mononeuritis multiplex, less often symmetric peripheral neuropathy. Rarely central nervous system involvement.
9) Gastrointestinal manifestations: Abdominal pain, diarrhea, bleeding from ulcerations.
10) Genitourinary tract manifestations: Bleeding from ulcerations.
11) Cardiac manifestations: Most frequently pericarditis with pericardial effusion. Rarely angina, endocarditis, or myocarditis.
GPA often starts with general symptoms (fever of unknown origin in ~50% of patients) and symptoms from the upper respiratory tract (70%), lungs (45%), and kidneys (<20%). The course is variable, ranging from indolent and mild (often without renal involvement) to rapidly progressive, life-threatening, and involving multiple organs.
1. Laboratory tests: Positive serum proteinase 3 (PR3) ANCA (in 80%-90% of patients; specificity, 98%). Additionally, there are often elevations in the erythrocyte sedimentation rate and C-protein levels, normocytic anemia, leukocytosis (in some cases >20,000/microL), thrombocytosis, and features of glomerulonephritis.
2. Imaging studies: Radiographs and computed tomography (CT) reveal features of chronic sinusitis, frequently accompanied by bone destruction. In the lungs, disseminated infiltrates (these may resolve or change their locations), necrotic nodules, and interstitial lesions (presenting as linear opacifications) are usually observed.
3. Histologic examination: Granulomatous inflammation, necrosis, and inflammatory lesions in vessel walls. Biopsy specimens are taken from an involved organ, ideally the upper respiratory tract or kidney. Usually it is difficult to establish the diagnosis of GPA solely on the basis of histology.
Diagnostic criteria are based on the characteristic histologic features in a patient with typical pulmonary lesions and/or urinalysis findings and a positive ANCA test result (PR3 ANCA/cytoplasmic ANCA [c-ANCA]). In rare cases of patients with a limited form of the disease, ANCAs may be negative.
Differential diagnosis should include:
1) Other causes of pulmonary-renal syndrome: Microscopic polyangiitis (most frequently), eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), cryoglobulinemic vasculitis, IgA vasculitis (Henoch-Schönlein purpura; rare), other small-vessel vasculitides (eg, serum sickness), systemic lupus erythematosus, vasculitis associated with anti-glomerular basement membrane antibodies.
2) Causes of alveolar hemorrhage other than vasculitis (see Diffuse Alveolar Hemorrhage).
3) Polyarteritis nodosa.
4) Glomerulonephritis with crescents and no immune deposits.
1. Remission induction is started in the acute phase of the disease. After achieving remission, maintenance treatment is initiated.
2. Treatment depends on the category of vasculitis (according to the European Vasculitis Study categorization of ANCA-associated vasculitides), which may be:
1) Localized: Limited to the upper or lower respiratory tract with no systemic symptoms or other organ involvement.
2) Early systemic: Any other manifestations but with no organ or life-threatening features.
3) Generalized: Renal or other organ-threatening disease (creatinine level <500 micromol/L [5.6 mg/dL]).
4) Severe: Renal or other vital organ failure (creatinine level >500 micromol/L).
5) Refractory disease: Progression despite treatment with glucocorticoids and cyclophosphamide.
1. Generalized disease (including severe disease): In severe, newly-diagnosed disease (GPA as well as microscopic polyangiitis or eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)), remission induction therapy with a combination of cyclophosphamide and high-dose glucocorticoids is recommended.
1) Cyclophosphamide in IV pulses 15 mg/kg (maximum, 1200 mg/d). It is recommended that the first 3 pulses should be administered every 2 weeks and the subsequent 3 to 6 pulses every 3 weeks (for a total of 3-6 months). As an alternative, oral treatment at a dose of 2 mg/kg/d (maximum, 200 mg/d) may be used, but the IV route is preferred due to the lower toxicity and cumulative dose (the lifetime cumulative dose of cyclophosphamide should not be >25 g). In the case of renal failure and in elderly patients reduce the dose by 25% to 50%. In all patients we suggest prophylaxis of Pneumocystis jirovecii infection (sulfamethoxazole/trimethoprim 800/160 mg 1 tablet 3 times a week or 800/40 mg daily) to be continued until at least 3 months after cessation of cyclophosphamide.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the presence of small observational studies with no patient-important outcomes, imprecision, indirectness, and risk of bias. Additionally, there was indirectness in the randomized controlled trial with HIV patients. Jarrousse B, Guillevin L, Bindi P, et al. Increased risk of Pneumocystis carinii pneumonia in patients with Wegener's granulomatosis. Clin Exp Rheumatol. 1993 Nov-Dec;11(6):615-21. Erratum in: Clin Exp Rheumatol 1994 Jan-Feb;12(1):117. PubMed PMID: 8299252. Stern A, Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev. 2014 Oct 1;(10):CD005590. doi: 10.1002/14651858.CD005590.pub3. Review. PubMed PMID: 25269391. Suryaprasad A, Stone JH. When is it safe to stop Pneumocystis jiroveci pneumonia prophylaxis? Insights from three cases complicating autoimmune diseases. Arthritis Rheum. 2008 Jul 15;59(7):1034-9. doi: 10.1002/art.23822. PubMed PMID: 18576286.
2) Glucocorticoids: Prednisone 1 mg/kg/d orally or IV usually for 1 month is recommended, then the dose is tapered down. According to the British Society for Rheumatology, the maximum dose is 60 mg; another glucocorticoid at an equivalent dose may be used. In severe cases IV pulses of methylprednisolone 500 to 1000 mg/d may be used for the first 2 to 3 days in cases of life-threatening disease or major organ involvement.Evidence 2Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the fact that the studies were actually primarily evaluating cyclophosphamide and methotrexate (indirectness). Additionally, there is a lack of studies directly comparing different doses of glucocorticoids and little data assessing the effectiveness of IV methylprednisolone (imprecision). De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005 Aug;52(8):2461-9. PubMed PMID: 16052573. Guillevin L, Cordier JF, Lhote F, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener's granulomatosis. Arthritis Rheum. 1997 Dec;40(12):2187-98. PubMed PMID: 9416856.
3) As stated in the chapter on microscopic polyangiitis, rituximab (with high-dose glucocorticoids) is preferred over cyclophosphamide in patients at increased risk of infection or in younger patients who are planning a pregnancy, with the efficacy equal to that of cyclophosphamide.Evidence 3Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Remark: A strong rather than weak recommendation places high value on differences in efficacy and less value on cost. High Quality of Evidence (high confidence that we know true effects of the intervention). Applicable when comparing the efficacy of cyclophosphamide versus rituximab. Stone JH, Merkel PA, Spiera R, et al; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905. PubMed PMID: 20647199; PubMed Central PMCID: PMC3137658. Jones RB, Tervaert JW, Hauser T, et al; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010 Jul 15;363(3):211-20. doi: 10.1056/NEJMoa0909169. PubMed PMID: 20647198. Administer 375 mg/m2 once weekly for 4 weeks or 2 doses of 1 g in a 2-week interval.
4) Plasmapheresis is not recommended as a first-line therapy. Preliminary data from a large clinical trial of plasmapheresis in GPA did not show benefit but the full results of this are not expected until late 2019.Evidence 4Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision between treatment protocols in the meta-analysis, small size of the randomized controlled trials, and risk of bias due to study design (nonblinded). Klemmer PJ, Chalermskulrat W, Reif MS, Hogan SL, Henke DC, Falk RJ. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis. 2003 Dec;42(6):1149-53. Review. PubMed PMID: 14655185. Walsh M, Catapano F, Szpirt W, et al. Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: a meta-analysis. Am J Kidney Dis. 2011 Apr;57(4):566-74. doi: 10.1053/j.ajkd.2010.10.049. Epub 2010 Dec 30. Review. PubMed PMID: 21194817; PubMed Central PMCID: PMC3062650. In these cases, we suggest 7 plasma exchanges (60 mL/kg or 1 plasma volume exchange) within 14 days with albumin as the replacement fluid except in patients who are bleeding or are at high risk of bleeding.
2. Localized and early systemic disease (ie, without organ- or life-threatening features): Cyclophosphamide, which we prefer for its efficacy, may be replaced with oral methotrexate.Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Stone JH, Tun W, Hellman DB. Treatment of non-life threatening Wegener's granulomatosis with methotrexate and daily prednisone as the initial therapy of choice. J Rheumatol. 1999 May;26(5):1134-9. PubMed PMID: 10332980. De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005 Aug;52(8):2461-9. PubMed PMID: 16052573. Start from 15 mg/wk and administer it in combination with a glucocorticoid (dosage as above, or lower); the dose should be titrated up to 20 to 25 mg/wk over 1 to 2 months. Mycophenolate mofetil may also be used as an alternative to cyclophosphamide if methotrexate is not tolerated or contraindicated.Evidence 6Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the small size of study and open-label design. Silva F, Specks U, Kalra S, et al. Mycophenolate mofetil for induction and maintenance of remission in microscopic polyangiitis with mild to moderate renal involvement--a prospective, open-label pilot trial. Clin J Am Soc Nephrol. 2010 Mar;5(3):445-53. doi: 10.2215/CJN.06010809. Epub 2010 Jan 21. PubMed PMID: 20093349; PubMed Central PMCID: PMC2827580. Hu W, Liu C, Xie H, Chen H, Liu Z, Li L. Mycophenolate mofetil versus cyclophosphamide for inducing remission of ANCA vasculitis with moderate renal involvement. Nephrol Dial Transplant. 2008 Apr;23(4):1307-12. Epub 2007 Dec 8. PubMed PMID: 18065810.
3. Refractory disease (remission cannot be achieved with conventional treatments or disease recurs): If cyclophosphamide is ineffective, rituximab may be used in combination with glucocorticoids for remission induction.Evidence 7Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of the studies (retrospective cohort). Jones RB, Ferraro AJ, Chaudhry AN, et al. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2009 Jul;60(7):2156-68. doi: 10.1002/art.24637. PubMed PMID: 19565480. Cartin-Ceba R, Golbin JM, Keogh KA, et al. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): ten-year experience at a single center. Arthritis Rheum. 2012 Nov;64(11):3770-8. doi: 10.1002/art.34584. PubMed PMID: 22730028. Other possible treatments include intravenous immunoglobulin, leflunomide, antithymocyte immunoglobulin, and anti-CD52 therapy.
4. End-stage renal disease: Renal replacement therapy (dialysis or transplantation).
Maintenance treatment is continued for ≥18 months (usually up to 5 years) after clinical remission has been achieved, particularly in patients with persistent PR3 ANCA positivity. In patients without persistent PR3 ANCA positivity, including patients with microscopic polyangiitis, maintenance treatment is usually shorter but should last ≥18 months.
1) Azathioprine 2 mg/kg/d or methotrexate 20 to 25 mg/wk. Leflunomide 20 mg/d or mycophenolate mofetil 2 to 3 g/d may also be used if the two former medications are not tolerated or contraindicated.Evidence 8Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Applies to methotrexate, azathioprine, and leflunomide as remission maintenance treatment. Jayne D, Rasmussen N, Andrassy K, et al; European Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3;349(1):36-44. PubMed PMID: 12840090. Pagnoux C, Mahr A, Hamidou MA, et al; French Vasculitis Study Group. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008 Dec 25;359(26):2790-803. doi: 10.1056/NEJMoa0802311. PubMed PMID: 19109574. Metzler C, Miehle N, Manger K, et al; German Network of Rheumatic Diseases. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's granulomatosis. Rheumatology (Oxford). 2007 Jul;46(7):1087-91. Epub 2007 May 22. PubMed PMID: 17519271. These treatments should probably be continued for a minimum of 18 months after achieving successful remission.Evidence 9Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of the study (retrospective cohort), risk of bias, and small sample size in the short-term therapy group (<18 months). Springer J, Nutter B, Langford CA, Hoffman GS, Villa-Forte A. Granulomatosis with polyangiitis (Wegener's): impact of maintenance therapy duration. Medicine (Baltimore). 2014 Mar;93(2):82-90. doi: 10.1097/MD.0000000000000020. PubMed PMID: 24646464; PubMed Central PMCID: PMC4616311.
2) Rituximab 500 mg every 4 to 6 months, assuming the cost is acceptable, is a preferred alternative to above treatment, particularly in patients with PR3 ANCA-positive GPA.Evidence 10Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Guillevin L, Pagnoux C, Karras A, et al; French Vasculitis Study Group. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014 Nov 6;371(19):1771-80. doi: 10.1056/NEJMoa1404231. PubMed PMID: 25372085.
3) Glucocorticoids: The dose may be tapered (down to ≥15 mg/d over the first 2-3 months, then to ≤10 mg/d at around 3-6 months, and then down to discontinuation) in patients who continue to be in remission. In case of recurrence the dose can be increased again.
4) Sulfamethoxazole/trimethoprim 800/160 mg bid may be used as an adjunct to azathioprine and leflunomide or after stopping the maintenance immunosuppressive treatment.Evidence 11Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. The only noted advantage of adjunct sulfamethoxazole/trimethoprim was the reduction in upper airway/ear, nose, and throat relapse. Pierrot-Deseilligny Despujol C, Pouchot J, Pagnoux C, Coste J, Guillevin L. Predictors at diagnosis of a first Wegener's granulomatosis relapse after obtaining complete remission. Rheumatology (Oxford). 2010 Nov;49(11):2181-90. doi: 10.1093/rheumatology/keq244. Epub 2010 Jul 31. PubMed PMID: 20675708. Reinhold-Keller E, De Groot K, Rudert H, Nölle B, Heller M, Gross WL. Response to trimethoprim/sulfamethoxazole in Wegener's granulomatosis depends on the phase of disease. QJM. 1996 Jan;89(1):15-23. PubMed PMID: 8730339. Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. N Engl J Med. 1996 Jul 4;335(1):16-20. PubMed PMID: 8637536.
Persistently elevated or increasing levels of ANCA are a risk factor for relapse.
Treatment with cyclophosphamide achieves remission in >90% of patients and 8-year survival rates are >80%. Relapse usually occurs within a year from discontinuation of immunosuppressive treatment; in >50% of patients it occurs within 5 years. The most common causes of death are complications of the disease (renal or respiratory failure) or adverse effects of treatment (severe infection).