Comparisons of Guidelines and Recommendations on Managing Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
2018; Elsevier BV; Volume: 3; Issue: 5 Linguagem: Inglês
10.1016/j.ekir.2018.05.007
ISSN2468-0249
AutoresDuvuru Geetha, Qiuyu Jin, Jennifer Scott, Zdenka Hrušková, Mohamad Hanouneh, Mark A. Little, Vladimı́r Tesař, Philip Seo, David Jayne, Christian Pagnoux,
Tópico(s)Sarcoidosis and Beryllium Toxicity Research
ResumoAntineutrophil cytoplasmic antibodies−associated vasculitis (AAV) is associated with high morbidity or mortality, especially if not promptly diagnosed and treated. Many inroads have been made in the understanding of the pathophysiology that leads to exploration of novel therapies. Randomized controlled trials over the last 2 decades have better delineated and expanded therapeutic options and set the stage for an evidence-based approach. Since 2014, 4 scientific societies have systematically reviewed the existing data and have formulated evidence-based recommendations for the management of AAV. These recommendations cover diagnosis, remission induction and maintenance treatment, and prevention of long-term complications. This review is a comparative analysis of the recently published recommendations of the European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association, the British Society of Rheumatology, the Canadian Vasculitis Research Network, and the Brazilian Society of Rheumatology, and aims to determine common ground among them and highlights the differences among the recommendations. Antineutrophil cytoplasmic antibodies−associated vasculitis (AAV) is associated with high morbidity or mortality, especially if not promptly diagnosed and treated. Many inroads have been made in the understanding of the pathophysiology that leads to exploration of novel therapies. Randomized controlled trials over the last 2 decades have better delineated and expanded therapeutic options and set the stage for an evidence-based approach. Since 2014, 4 scientific societies have systematically reviewed the existing data and have formulated evidence-based recommendations for the management of AAV. These recommendations cover diagnosis, remission induction and maintenance treatment, and prevention of long-term complications. This review is a comparative analysis of the recently published recommendations of the European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association, the British Society of Rheumatology, the Canadian Vasculitis Research Network, and the Brazilian Society of Rheumatology, and aims to determine common ground among them and highlights the differences among the recommendations. Antineutrophil cytoplasmic antibodies (ANCAs)−associated vasculitides (AAV) are a heterogeneous group of systemic necrotizing small vessel vasculitides. More than 90% of AAV patients have circulating ANCAs. AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Several landmark trials in the last 2 decades have harmonized and optimized the treatment of AAV, which was a frequently fatal disease before the introduction of high-dose glucocorticoids (GCs) and cyclophosphamide (CYC). More recent concerns have been the cumulative toxicity of these agents and management of a chronic relapsing disease course. More effective and safer induction and maintenance therapy regimens have emerged as a result of these trials. Guidelines for management of AAV have been published by various medical societies. This review compares 4 guidelines published in the English language, from the: (i) British Society for Rheumatology (BSR) and British Health Professionals for Rheumatology (BHPR) (2014),1Ntatsaki E. Carruthers D. Chakravarty K. et al.BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis.Rheumatology (Oxford). 2014; 53: 2306-2309Crossref PubMed Scopus (205) Google Scholar updated from their 2007 guidelines2Lapraik C. Watts R. Bacon P. et al.BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis.Rheumatology (Oxford). 2007; 46: 1615-1616Crossref PubMed Scopus (151) Google Scholar; (ii) the Canadian Vasculitis Research Network (CanVasc) (2015)3McGeoch L. Twilt M. Famorca L. et al.CanVasc recommendations for the management of antineutrophil cytoplasm antibody-associated vasculitides.J Rheumatol. 2016; 43: 97-120Crossref PubMed Scopus (60) Google Scholar developed by members of the core committee of the CanVasc research network; (iii) the European League Against Rheumatism (EULAR)/European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) (2016),4Yates M. Watts R.A. Bajema I.M. et al.EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.Ann Rheum Dis. 2016; 75: 1583-1594Crossref PubMed Scopus (729) Google Scholar developed by an international task force representing EULAR, ERA, and the European Vasculitis Society (EUVAS), updated from their 2008 guidelines5Mukhtyar C. Guillevin L. Cid M.C. et al.European Vasculitis Study GroupEULAR recommendations for the management of primary small and medium vessel vasculitis.Ann Rheum Dis. 2009; 68: 310-317Crossref PubMed Scopus (738) Google Scholar; and (iv) the Brazilian Society of Rheumatology (SBR) (2017), which focused only on induction therapy of AAV (Table 1).6Souza A.W.S. Calich A.L. Mariz H.A. et al.Recommendations of the Brazilian Society of Rheumatology for the induction therapy of ANCA-associated vasculitis.Rev Bras Reumatol Engl Ed. 2017; 57 Suppl 2: 484-496Crossref PubMed Scopus (17) Google Scholar There are no guidelines published from the United States, and although the American College of Rheumatology did not endorse the recently published EULAR/ERA-EDTA guidelines, an American College of Rheumatology representative contributed to these guidelines. The strength of the recommendations made by BSR/BHPR, EULAR/ERA-EDTA, and CanVasc is based on the categories of evidence defined by EULAR standardized operating procedures, graded from A (highest) to D (lowest),7Dougados M. Betteridge N. Burmester G.R. et al.EULAR standardised operating procedures for the elaboration, evaluation, dissemination, and implementation of recommendations endorsed by the EULAR standing committees.Ann Rheum Dis. 2004; 63: 1172-1176Crossref PubMed Scopus (181) Google Scholar and the strength of recommendations made by BSR is based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system8Guyatt G.H. Oxman A.D. Kunz R. et al.GRADE Working GroupGoing from evidence to recommendations.BMJ. 2008; 336: 1049-1051Crossref PubMed Google Scholar and graded from A (highest) to D (lowest). Our aim was to determine the common ground among the recommendations and highlight the differences among them.Table 1Features of the compared guidelinesSocietyPublication yearStake holdersGeographyBSR/BHPR2014Vasculitis physician experts from multiple specialties and allied health care professional representativesUnited KingdomEULAR/ERA-EDTA2015International task force representing EULAR, ERA, and EUVAS, and including physicians (internists, specialists, and pathologists), patients, nursesEuropeCanVasc2016Vasculitis physician experts from multiple specialtiesCanadaSBR2017RheumatologistsBrazilBHPR, British Health Professionals in Rheumatology; BSR, British Society for Rheumatology; CanVasc, Canadian Vasculitis research network; ERA-EDTA, European Renal Association-European Dialysis and Transplant Association; EULAR, European League Against Rheumatism; EUVAS, European Vasculitis Society; SBR, Brazilian Society of Rheumatology. Open table in a new tab BHPR, British Health Professionals in Rheumatology; BSR, British Society for Rheumatology; CanVasc, Canadian Vasculitis research network; ERA-EDTA, European Renal Association-European Dialysis and Transplant Association; EULAR, European League Against Rheumatism; EUVAS, European Vasculitis Society; SBR, Brazilian Society of Rheumatology. CanVasc and EULAR/ERA-EDTA both recommend obtaining tissue biopsy at diagnosis, if possible; EULAR/ERA-EDTA also recommends biopsy at relapse. BSR/BHPR and CanVasc specifically note that ANCA testing should be performed with indirect immunofluorescence and enzyme-linked immunosorbent assay at diagnosis; BSR/BHPR also recommends testing at relapse, at change of therapy, and at every 6 months during treatment, and annually while off treatment. Indirect immunofluorescence alone is not sufficient for diagnosis for AAV due to the ability of autoantibodies against antigens other than PR3 and MPO to cause a positive staining pattern. A new international consensus statement on ANCA testing recommends initial testing for suspected AAV with immunoassays for PR3 ANCA and MPO ANCA replacing the use of indirect immunofluorescence.9Bossuyt X. Cohen Tervaert J. Arimura Y. et al.Position paper: Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis.Nat Rev Rheumatol. 2017; 13: 683-692Crossref PubMed Scopus (208) Google Scholar All 4 guidelines divide patients into those with life- or organ-threatening disease and those without. CanVasc specifically refers to these groups as severe versus nonsevere, which is terminology also used in the EULAR guidelines. The distinction between the 2 categories varies somewhat. For example, CanVasc defines severe disease as the "presence of life- or major organ-threatening manifestations, including severe and progressive kidney involvement; severe alveolar hemorrhage; severe GI, cardiac, CNS, and/or eye involvements; or any other manifestations considered severe enough to require induction treatment with CYC or RTX."3McGeoch L. Twilt M. Famorca L. et al.CanVasc recommendations for the management of antineutrophil cytoplasm antibody-associated vasculitides.J Rheumatol. 2016; 43: 97-120Crossref PubMed Scopus (60) Google Scholar, 4Yates M. Watts R.A. Bajema I.M. et al.EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.Ann Rheum Dis. 2016; 75: 1583-1594Crossref PubMed Scopus (729) Google Scholar In contrast, BSR/BHPR seems to group more patients into nonsevere disease as "those with no evidence of organ damage who may be considered for alternative induction therapy with MTX or MMF," and all other patients should be considered to have severe disease and treated with CYC or rituximab (RTX). In addition to these categorizations, CanVasc refers to the use of the 5-factor score for prognostication of EGPA and MPA. The recommendations made by the 4 guidelines are summarized in Table 2. The protocols for the 3 landmark trials for induction therapy are depicted in Figure 1.Table 2Induction therapy in severe disease and refractory diseaseCategoryCommon viewDifferencesSevere diseaseCYCCYC with high-dose steroids for first-line induction is universally recommended.GC + CYC therapy should be continued for 3−6 mo, then switched to a less toxic maintenance therapy when remission is achieved. Dosing adjustments should be made for age and renal function (BSR, CanVasc, SBR)FormulationSBR and CanVasc: Either oral or i.v. pulsed CYC.BSR and EULAR: Favor i.v. pulsed CYCDosingBSR, SBR: Standard 15 mg/kg, max 1.2 g (SBR)1.5 g (BSR) per pulse, first 3 pulses at 2-wk intervals, then every 3 wks for total of 3−6 mosEULAR: not specified, but refers to CYCLOPS trial, which is same as the precedingRTXAll 4 guidelines recommend RTX with high-dose steroids for first-line induction in patients in whom CYC is contraindicated or not preferredFirst line RTX:BSR and EULAR: recommend RTX first-line in general for all AAV patients; EULAR notes that the data are weakest among patients with EGPA.SBR: recommends RTX as an alternative in patients in whom CYC is contraindicated or not preferredCanVasc: recommends GC + RTX as first-line remission induction in patients with severe GPA or MPA in whom CYC is contraindicated or not preferredDosing:SBR: rituximab should be given at 375 mg/m2 weekly for 4 wks, or in 2 infusions 2 wks apart at a dose of 1 g.BSR and CanVasc: recommend 375 mg/m2 weekly for 4 wksGC dosingEvery patient should receive systemic GCs. In severe disease, patient may be started first on i.v. pulse methylprednisoloneOral GC dosing and schedule:BSR: start oral prednisolone at 1.0 mg/kg per day (max, 60 mg/d), tapered to 15 mg per day at 12 wks.SBR: start prednisone at 0.5-1.0 mg/kg per day (max, 80 mg/d) for 1−4 wks, taper by 10 mg for 2−4 wks until 20 mg/d, then reduce by 2.5−5.0 mg every 2−4 wks until full withdrawal.CanVasc: start prednisone equivalent at 1.0 mg/kg per day (max, 60−80 mg/d) for 1 mo, then gradually taperedEULAR: 1.0 mg/kg per day (max, 80 mg/d)i.v. pulse methylprednisolone dosing:BSR: 200−500 mg/d before or with first 2 doses of CYCCanVasc: 500−1000 mg/d for 1−3 daysSBR: 500−1000 mg/d or 15 mg/kg per day for 1−3 daysEULAR: not specifiedi.v. IgSBR: patients with infection and persistent disease, with disease refractory to GC + CYC, or contraindications to CYC or RTX should be given i.v. IgCanVasc: there is insufficient evidence for any specific recommendation of i.v. Ig, but it could have a role in certain subgroups such as adjunct in refractory disease, pregnant women in whom other immunosuppressants are contraindicated, and those with current severe infection or recurrent severe infectionsEULAR: i.v. Ig can be given as an adjunct therapy in the refractory setting.Other agentsEtanercept should not be used to treat AAV; other TNF-α inhibitors have limited evidence (BSR, CanVasc, SBR)SBR: recommends against azathioprine in the remission induction settingBSR, CanVasc: Possible experimental options for refractory disease include mepolizumab for patients with EGPA, alemtuzumab (anti-CD52).BSR: other experimental options include gusperimus and leflunomide.Refractory diseaseAll refractory patients should be referred to a vasculitis center (BSR, CanVasc, EULAR)Patients who received CYC:BSR and EULAR: all refractory patients with severe disease who have failed CYC should receive RTX.CanVasc: Severe GPA/MPA patients in whom CYC failed should receive RTX.Patients who received RTX:EULAR: refractory patients who received RTX should now receive CYC.These patients can be considered for more experimental treatments at a vasculitis referral center (BSR, CanVasc). Other strategies include adjunct i.v. Ig and switching from pulsed to oral CYC (when RTX is unavailable/cannot be administered). (EULAR).BSR, British Society for Rheumatology; CanVasc, Canadian Vasculitis research network; CYC, cyclophosphamide; EULAR, European League Against Rheumatism; GC, glucocorticoids; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; RTX, rituximab; SBR, Brazilian Society of Rheumatology. Open table in a new tab BSR, British Society for Rheumatology; CanVasc, Canadian Vasculitis research network; CYC, cyclophosphamide; EULAR, European League Against Rheumatism; GC, glucocorticoids; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; RTX, rituximab; SBR, Brazilian Society of Rheumatology. CYC use for remission induction received a grade A recommendation across all 4 guidelines. The preference for i.v. CYC by BSR/BHPR is based on the results of CYCLOPS (Cyclophosphamide Oral versus Pulsed)10de Groot K. Harper L. Jayne D.R.W. et al.Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial.Ann Intern Med. 2009; 150: 670-680Crossref PubMed Scopus (692) Google Scholar trial, which demonstrated lower cumulative exposure in the i.v. CYC arm and in earlier randomized controlled trials.11de Groot K. Adu D. Savage C.O. EUVAS (European Vasculitis Study Group)The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review.Nephrol Dial Transplant. 2001; 16: 2018-2027Crossref PubMed Scopus (301) Google Scholar EULAR/ERA-EDTA also favored i.v. CYC for this reason, as well as due to a reduced risk of CYC-related bladder complications. SBR and CanVasc recommend either oral or i.v. pulsed CYC. CanVasc also notes the potential lower rate of relapse on longer term follow-up with oral CYC. The standard dosing for oral CYC is 2 mg/kg per day (maximum 200 mg/d), and dosing for i.v. CYC is 15 mg/kg (maximum 1.2 g/pulse), given 3 times 2 weeks apart, and then once every 3 weeks for 3 to 6 months (CYCLOPS). RTX is generally recommended as an alternative to CYC for remission induction of AAV. BSR/BHPR (grade B recommendation) and EULAR/ERA-EDTA (grade A recommendation) recommend it as a first-line alternative without particular restrictions, although EULAR notes that the data remain weakest among patients with EGPA. SBR also recommends it as an alternative, highlighting a particular role in patients in whom CYC is contraindicated or not preferred due to fertility or other concerns, or in those with relapsing disease. CanVasc is the most restrictive, specifying RTX as a first-line remission induction in patients with severe GPA/MPA disease in whom CYC is contraindicated and/or not preferred. None of the guidelines recommend against RTX as first-line induction treatment. The main drawbacks cited are access and/or cost barriers. GCs are an ubiquitous part of front-line induction therapy. Patients with severe disease may be administered i.v. pulse methylprednisolone initially. All guidelines acknowledge that the data on the benefits of i.v. methylprednisolone are limited. BSR/BHPR recommends 250 to 500 mg pulse before or with the first 2 CYC infusions. CanVasc and SBR recommend using i.v. methylprednisone 500 to 1000 mg/d for 3 days preceding oral prednisone in life-threatening and/or organ-threatening AAV. CanVasc gives a grade B recommendation, and SBR gives a grade C recommendation for use of i.v. methylprednisone. EULAR does not provide specific recommendations on the use of i.v. methylprednisolone. Patients should be started on oral prednisone equivalent to 0.5 to 1 mg/kg per day with a maximum of 60 to 80 mg/d, and then tapered. The CanVasc discusses prednisone-tapering protocols in the RAVE (rituximab for ANCA-associated vasculitis)12Stone J.H. Merkel P.A. Spiera R. et al.Rituximab versus cyclophosphamide for ANCA-associated vasculitis.N Engl J Med. 2010; 363: 221-232Crossref PubMed Scopus (1876) Google Scholar and RITUXVAS (rituximab versus cyclophosphamide in ANCA-associated vasculitis)13Jones R.B. Cohen Tervaert J.W. et al.Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.N Engl J Med. 2010; 363: 211-220Crossref PubMed Scopus (1195) Google Scholar trials in the supplement13Jones R.B. Cohen Tervaert J.W. et al.Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.N Engl J Med. 2010; 363: 211-220Crossref PubMed Scopus (1195) Google Scholar and recommends that a prednisone dose of 1 mg/kg per day be continued for a maximum of 1 month, with a gradual taper and dose adjustment based on the clinical course of the patient (recommendation C). The EULAR/ERA-EDTA recommends a target dose of 10 to 15 mg of prednisone daily after 12 weeks of treatment. BSR recommends rapid tapering for prednisone 15 mg/d at 12 weeks. SBR recommends a slow prednisone-tapering regimen, with an initial daily dose of 0.5 to 1.0 mg/kg per day (maximum 80 mg/d) for 1 to 4 weeks, followed by tapering 10 mg every 2 to 4 weeks until 20 mg/d. Afterward, they suggest that dose reduction should be 2.5 to 5.0 mg every 2 to 4 weeks until complete withdrawal. The initial starting dose of prednisone received a grade B recommendation across all guidelines, whereas the tapering regimen received a grade C from CanVasc and BSR/BHPR and grade D from SBR. Regarding the duration of GC therapy, there are differences across the guidelines. CanVasc states low-dose GCs should be part of the initial maintenance therapy and notes that there is not enough evidence yet to support the optimal duration of low-dose GCs. EULAR does not provide recommendations on GC duration. SBR recommends that the duration of GC therapy should be at least 6 months, and, in some instances, it may be up to 1 or 2 years. Longer duration of GCs may be necessary in relapsing patients (recommendation A by BSR/BHPR and recommendation B by BSR). CanVasc states that plasma exchange may be a reasonable adjuvant therapy for patients who deteriorate due to active vasculitis despite ongoing remission induction therapy with high-dose GCs plus CYC or RTX. However, there is insufficient evidence to recommend plasma exchange as first-line therapy in any patient with AAV (grade D recommendation). BSR/BHPR and EULAR/ERA-EDTA recommend that plasma exchange should be used along with CYC and GCs in patients presenting with severe renal failure with serum creatinine >500 μmol/l (grade B recommendation) or life-threatening manifestations, such as pulmonary hemorrhage (grade C recommendation). SBR recommends use of plasma exchange along with GCs and CYC in patients with serum creatinine >5.8 mg/dl (grade A recommendation) and notes there is insufficient evidence to support plasma exchange to treat AAV patients who present with alveolar hemorrhage (Table 3).Table 3Recommendations for use of plasma exchange in induction therapy of antineutrophil cytoplasmic antibodies−associated vasculitidesDisease manifestationCommon viewDifferencesPlasmapheresisRapidly progressive glomerulonephritisCanVasc states there is insufficient evidence to recommend plasmapheresis for patients with severe renal or pulmonary involvement, but it may be a reasonable adjuvant if a patient is refractory to high dose GC + CYC/RTX.BSR, SBR, and EULAR recommend consideration of plasma exchange for RPGN with serum Cr greater than ∼500 μmol/l (5.7 mg/dl).PlasmapheresisDiffuse alveolar hemorrhageThere is insufficient evidence, but may be considered/possibly of benefit as an adjuvant when patients are in this setting and refractory to standard GC + CYC/RTX (all 4 guidelines)BSR, British Society for Rheumatology; CanVasc, Canadian Vasculitis research network; CYC, cyclophosphamide; EULAR, European League Against Rheumatism; GC, glucocorticoids; GPA, granulomatosis with polyangiitis; RTX, rituximab; SBR, Brazilian Society of Rheumatology. Open table in a new tab BSR, British Society for Rheumatology; CanVasc, Canadian Vasculitis research network; CYC, cyclophosphamide; EULAR, European League Against Rheumatism; GC, glucocorticoids; GPA, granulomatosis with polyangiitis; RTX, rituximab; SBR, Brazilian Society of Rheumatology. CanVasc and EULAR/ERA-EDTA state that the ongoing PEXIVAS (Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody Associated Vasculitis) trial may provide more definitive answers regarding efficacy and safety of plasma exchange in AAV. Generally, patients with nonsevere and nonorgan-threatening disease are recommended a milder regimen than CYC or RTX. BSR/BHPR and EULAR guidelines recommend systemic GCs with either methotrexate (MTX) or mycophenolate mofetil (MMF) (grade B recommendation for MTX and grade C recommendation for MMF), whereas CanVasc and SBR only recommend GCs with MTX (grade A recommendation). The EULAR/ERA-EDTA guidelines emphasize that nonsevere and nonorgan-threatening had different meanings and listed organ-specific scenarios when MTX use was inappropriate. All guidelines recommend dose adjustment of MTX for renal function. EULAR/ERA-EDTA states that MTX can be used in the absence of renal involvement and BSR/BHPR states that MTX should not be used in patients with moderate or severe renal involvement (grade B recommendation). CanVasc recommends dose adjustment when the glomerular filtration rate (GFR) is between 50 and 80 ml/min per square meter, to consider alternative therapy when GFR is <50 ml/min per square meter, and to avoid use when GFR is <10 ml/min per square meter. SBR recommends that the MTX dose should be decreased by 50% in patients with GFRs of 10 and 50 ml/min per square meter and to avoid use when GFR is <10 ml/min per square meter (grade D recommendation). CanVasc states that it is acceptable to treat patients with nonsevere EGPA or MPA without renal involvement with GCs alone. It cites 2 studies from the French Vasculitis Study Group, which showed that GCs alone induced remission in a significant portion of patients—93% of patients with EGPA14Ribi C. Cohen P. Pagnoux C. et al.Treatment of Churg-Strauss syndrome without poor-prognosis factors: a multicenter, prospective, randomized, open-label study of seventy-two patients.Arthritis Rheum. 2008; 58: 586-594Crossref PubMed Scopus (240) Google Scholar and 79% of patients with MPA or polyarteritis nodosa15Ribi C. Cohen P. Pagnoux C. et al.Treatment of polyarteritis nodosa and microscopic polyangiitis without poor-prognosis factors: a prospective randomized study of one hundred twenty-four patients.Arthritis Rheum. 2010; 62: 1186-1197Crossref PubMed Scopus (145) Google Scholar—although there were with significant relapse rates. In these studies, patients in whom GCs failed or patients who relapsed would then receive azathioprine (AZA) or CYC, both of which were effective in that setting.14Ribi C. Cohen P. Pagnoux C. et al.Treatment of Churg-Strauss syndrome without poor-prognosis factors: a multicenter, prospective, randomized, open-label study of seventy-two patients.Arthritis Rheum. 2008; 58: 586-594Crossref PubMed Scopus (240) Google Scholar, 15Ribi C. Cohen P. Pagnoux C. et al.Treatment of polyarteritis nodosa and microscopic polyangiitis without poor-prognosis factors: a prospective randomized study of one hundred twenty-four patients.Arthritis Rheum. 2010; 62: 1186-1197Crossref PubMed Scopus (145) Google Scholar None of the other guidelines advocate use of GCs alone. Table 4 provides an overview of the common view and differences across these guidelines.Table 4Maintenance therapy and management of relapseCategoryCommon viewDifferencesMaintenancePatients with severe AAV in remission after GC + CYC should receive maintenance therapy with GC + an immunosuppressant drug, among which AZA and MTX are most universally recommended.Population who should receive maintenance therapy:BSR, CanVasc: severe AAV in remission after GC + CYCCanVasc: there is no clear evidence/consensus to guide decisions for mainteannce after RTXEULAR: not specifiedAgent:BSR: AZA or MTX in combination with GC. LEF or MMF may be alternatives. RTX is also an option. CanVasc: AZA or MTX, initially in combination with low-dose GC. LEF and MMF are second-line alternatives. RTX is also an option particularly in PR3-ANCA-positive GPA. TMP/SMX can be considered as adjuvant maintenance therapy after normal maintenance with an immunosuppressant in patients with GPA.EULAR: Patients with GPA/MPA should receive low-dose GC and AZA, RTX, MTX, or MMF (greatest consensus for AZA); those with EGPA should receive AZA. LEF is a second-line option. TMP/SMX can be considered as adjuvant therapy but is not recommended alone.Duration of immunosuppressant agent in general:BSR, EULAR: 24 mos after duration.CanVasc: 18 mos, but no clear evidence.Duration of immunosuppressant agent for PR3-ANCA+ patients:BSR: up to 5 yrsEULAR: evidence still pending, but 36 mosDuration of GCs:BSR: patients in remission after 1 yr can begin to taper GCs. After GCs are withdrawn, the other immunosuppressive agent can be tapered after 6 mos.- CanVasc: no clear evidence for GC durationRelapsePatients who have a severe relapse should receive GC + CYC or RTX (BSR, CanVasc, EULAR).Nonsevere relapse may be managed with increasing the dosage of GC in addition to optimizing current immunosuppressant agent (BSR, CanVasc, EULAR).Severe relapseBSR: Severe relapse should be treated with GC + CYC or RTX. If the patient is trying a second round of GC + CYC, the dose of GC should be increased; addition of i.v. methylprednisolone and PLEX can be considered. Also, drivers for relapse should be identified.CanVasc: Patients who already tried GC + CYC should receive RTX.EULAR: In general, due to the cumulative toxicity of CYC, RTX is recommended over CYC in relapsing disease.AAV, antineutrophil cytoplasmic antibodies (ANCA)−associated vasculitides; AZA, azathioprine; BSR, British Society for Rheumatology; CanVasc, Canadian Vasculitis research network; CYC, cyclophosphamide; EGPA, eosinophilic granulomatosis with polyangiitis; EULAR, European League Against Rheumatism; GC, glucocorticoids; GPA, granulomatosis with polyangiitis; LEF, leflunomide; MMF, mycophenolate mofetil; MPA, microscopic polyangiitis; MTX, methotrexate; RTX, rituximab; SBR, Brazilian Society of Rheumatology; TMP/SMX, trimethoprim/sulfamethoxazole. Open table in a new tab AAV, antineutrophil cytoplasmic antibodies (ANCA)−associated vasculitides; AZA, azathioprine; BSR, British Society for Rheumatology; CanVasc, Canadian Vasculitis research network; CYC, cyclophosphamide; EGPA, eosinophilic granulomatosis with polyangiitis; EULAR, European League Against Rheumatism; GC, glucocorticoids; GPA, granulomatosis with polyangiitis; LEF, leflunomide; MMF, mycophenolate mofetil; MPA, microscopic polyangiitis; MTX, methotrexate; RTX, rituximab; SBR, Brazilian Society of Rheumatology; TMP/SMX, trimethoprim/sulfamethoxazole. For patients with severe AAV who are in remission after successful induction therapy with GCs + CYC, maintenance therapy is universally recommended across all guidelines, except for SBR, which focuses on induction therapy only. CanVasc is the only guideline that specifically discusses patients who receive GCs + RTX as induction therapy, stating that there is no adequate evidence yet for recommending any specific approach. Remission is defined by EULAR/EUVAS as the complete absence of clinical disease activity, including vasculitis and granulomatous manifestations, whether patients are receiving immunosuppressive therapy or not. EULAR/ERA-EDTA recommends use of low-dose GCs in combination with azathioprine, RTX, MTX, or MMF (in this order of preference) fo
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