Combination treatment with rituximab, low-dose cyclophosphamide and plasma exchange for severe antineutrophil cytoplasmic antibody-associated vasculitis

Abstract

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis can present with life-threatening lung-kidney syndromes. However, many controlled treatment trials excluded patients with diffuse alveolar hemorrhage or severely impaired glomerular filtration rates, and so the optimum treatment in these cases is unclear. In this retrospective cohort study, we report the outcomes of 64 patients with life-threatening disease treated with a combination regimen of rituximab, low-dose intravenous cyclophosphamide, oral glucocorticoids, and plasma exchange. At entry, the median estimated glomerular filtration rate was 9 mL/min, 47% of patients required dialysis, and 52% had diffuse alveolar hemorrhage. All patients received a minimum of seven plasma exchanges, and the median cumulative doses of rituximab, cyclophosphamide, and glucocorticoid were 2, 3, and 2.6 g, respectively, at six months. A total of 94% of patients had achieved disease remission (version 3 Birmingham Vasculitis Activity Score of 0) at this time point, and 67% of patients who required dialysis recovered independent kidney function. During long-term follow-up (median duration 46 months), overall patient survival was 85%, and 69% of patients remained free from end-stage kidney disease, which compares favorably to a historic cohort with severe disease treated with a conventional induction regimen. Combination treatment was associated with prolonged B cell depletion and low rates of relapse; 87% of patients were in continuous remission at month 36. The serious infection rate during total follow-up was 0.28 infections/patient/year, suggesting that combination treatment is not associated with an enduring risk of infection. Thus, we suggest that combination immunosuppressive therapy may permit glucocorticoid avoidance and provide rapid and prolonged disease control in patients with severe ANCA-associated vasculitis. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis can present with life-threatening lung-kidney syndromes. However, many controlled treatment trials excluded patients with diffuse alveolar hemorrhage or severely impaired glomerular filtration rates, and so the optimum treatment in these cases is unclear. In this retrospective cohort study, we report the outcomes of 64 patients with life-threatening disease treated with a combination regimen of rituximab, low-dose intravenous cyclophosphamide, oral glucocorticoids, and plasma exchange. At entry, the median estimated glomerular filtration rate was 9 mL/min, 47% of patients required dialysis, and 52% had diffuse alveolar hemorrhage. All patients received a minimum of seven plasma exchanges, and the median cumulative doses of rituximab, cyclophosphamide, and glucocorticoid were 2, 3, and 2.6 g, respectively, at six months. A total of 94% of patients had achieved disease remission (version 3 Birmingham Vasculitis Activity Score of 0) at this time point, and 67% of patients who required dialysis recovered independent kidney function. During long-term follow-up (median duration 46 months), overall patient survival was 85%, and 69% of patients remained free from end-stage kidney disease, which compares favorably to a historic cohort with severe disease treated with a conventional induction regimen. Combination treatment was associated with prolonged B cell depletion and low rates of relapse; 87% of patients were in continuous remission at month 36. The serious infection rate during total follow-up was 0.28 infections/patient/year, suggesting that combination treatment is not associated with an enduring risk of infection. Thus, we suggest that combination immunosuppressive therapy may permit glucocorticoid avoidance and provide rapid and prolonged disease control in patients with severe ANCA-associated vasculitis. Anti–neutrophil cytoplasm antibody (ANCA)–associated vasculitis (AAV) is a multisystem disease that can present with life-threatening features, including diffuse alveolar hemorrhage (DAH) and rapidly progressive glomerulonephritis (GN).1Kitching A.R. Anders H.J. Basu N. et al.ANCA-associated vasculitis.Nat Rev Dis Primers. 2020; 6: 71Crossref PubMed Scopus (87) Google Scholar DAH is associated with early mortality in AAV, with 1-year survival varying from 50% to 82%, and progression to end-stage kidney disease (ESKD) is associated with significant long-term morbidity and mortality.2Haworth S.J. Savage C.O. Carr D. et al.Pulmonary haemorrhage complicating Wegener’s granulomatosis and microscopic polyarteritis.Br Med J (Clin Res Ed). 1985; 290: 1775-1778Crossref PubMed Scopus (116) Google Scholar, 3Lauque D. Cadranel J. Lazor R. et al.Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM”O”P)Microscopic polyangiitis with alveolar hemorrhage: a study of 29 cases and review of the literature.Medicine (Baltimore). 2000; 79: 222-233Crossref PubMed Scopus (219) Google Scholar, 4Hogan S.L. Nachman P.H. Wilkman A.S. et al.Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis.J Am Soc Nephrol. 1996; 7: 23-32Crossref PubMed Google Scholar, 5Gallagher H. Kwan J.T. Jayne D.R. Pulmonary renal syndrome: a 4-year, single-center experience.Am J Kidney Dis. 2002; 39: 42-47Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 6Moiseev S. Novikov P. Jayne D. Mukhin N. End-stage renal disease in ANCA-associated vasculitis.Nephrol Dial Transplant. 2017; 32: 248-253PubMed Google Scholar However, many randomized controlled trials in AAV excluded patients with severely impaired glomerular filtration rate (GFR) or those with significant DAH. Only the Methylprednisolone versus Plasma Exchange for Renal Vasculitis (MEPEX), Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis (RITUXVAS), and Plasma Exchange and Glucocorticoids for Treatment of AAV (PEXIVAS) studies, for example, enrolled those with an estimated GFR (eGFR) <15 ml/min, and most patients in these studies did not have concomitant alveolar hemorrhage.7Jayne D.R. Gaskin G. Rasmussen N. et al.Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis.J Am Soc Nephrol. 2007; 18: 2180-2188Crossref PubMed Scopus (773) Google Scholar, 8Jones R.B. Tervaert J.W. Hauser T. et al.Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.N Engl J Med. 2010; 363: 211-220Crossref PubMed Scopus (1109) Google Scholar, 9Walsh M. Merkel P.A. Peh C.A. et al.Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis.N Engl J Med. 2020; 382: 622-631Crossref PubMed Scopus (179) Google Scholar Thus, the optimum treatment for patients presenting with these life-threatening features is not clearly defined. We and others have previously reported successful outcomes using combination induction regimens incorporating both cyclophosphamide and rituximab in patients with kidney involvement in AAV; these were associated with rapid disease control, prolonged periods of disease-free survival, and the ability to rapidly taper glucocorticoids.10McAdoo S.P. Medjeral-Thomas N. Gopaluni S. et al.Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis.Nephrol Dial Transplant. 2018; 33: 899Crossref PubMed Scopus (12) Google Scholar, 11Cortazar F.B. Muhsin S.A. Pendergraft 3rd, W.F. et al.Combination therapy with rituximab and cyclophosphamide for remission induction in ANCA vasculitis.Kidney Int Rep. 2018; 3: 394-402Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 12Pepper R.J. McAdoo S.P. Moran S.M. et al.A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody-associated vasculitis.Rheumatology. 2019; 58: 373Crossref PubMed Scopus (6) Google Scholar However, our previous report using this approach did not include patients with severe disease treated with plasma exchange (PEX) in addition to immunosuppression, and the use of similar regimens has not been extensively described for severe AAV. Herein, we report the long-term outcomes of 64 patients with life-threatening disease who were treated with our previously published combination of rituximab, low-dose i.v. cyclophosphamide, and low-dose oral glucocorticoids, which was modified to incorporate the use of PEX, which was standard care for severe disease at our center during the study period (Table 1). We defined severe disease as presentation with DAH and/or severe kidney injury (i.e., serum creatinine >500 μmol/L [5.7 mg/dl] or the need for renal replacement therapy [RRT]) before commencing treatment. As such, this cohort represents patients with more severe disease than recent published controlled and cohort studies.Table 1Treatment protocolVariableAgentDosePlasma exchangeCommencing day 0 or 36 h after cytotoxic therapyAgainst 4.5% or 5% HAS (or FFP if risk of bleeding)Daily exchange ×7; 60 ml/kg (max, 4 L)CytotoxicDay 0I.v. cyclophosphamide10 mg/kg (max, 750 mg)Day 7I.v. rituximabaRituximab was initiated at completion of plasma exchange.1 gWeek 2I.v. cyclophosphamideI.v. rituximab10 mg/kg (max, 750 mg)1 gWeeks 4, 6, 8, and 10I.v. cyclophosphamide500 mgGlucocorticoid taperWeek 1Oral prednisolone1 mg/kg per day (max, 60 mg/d)bIf received i.v. glucocorticoid before referral, then starting dose may be reduced to 0.5 mg/kg per day.Week 225% Reduction45 mg/dWeek 333% Reduction30 mg/dWeek 433% Reduction20 mg/dWeek 625% Reduction15 mg/dWeek 1212.5 mg/dWeek 2010 mg/dMaintenanceFrom week 12Azathioprine2 mg/kg per dayMMF0.5–1 g daily if intolerantAdjuvant therapyPJP prophylaxisCotrimoxazole or pentamidine nebulizers480 mg/d300 mg/mo (if intolerant)Peptic ulcer prophylaxisProton-pump inhibitorBone prophylaxisVitamin D and calcium supplementationLatent TB treatment (in those from high-risk areas)Isoniazid and pyridoxine150 mg/d50 mg/wkFFP, fresh-frozen plasma; HAS, human albumin solution; max, maximum; MMF, mycophenolate mofetil; PJP, Pneumocystis jirovecii pneumonia; TB, tuberculosis.a Rituximab was initiated at completion of plasma exchange.b If received i.v. glucocorticoid before referral, then starting dose may be reduced to 0.5 mg/kg per day. Open table in a new tab FFP, fresh-frozen plasma; HAS, human albumin solution; max, maximum; MMF, mycophenolate mofetil; PJP, Pneumocystis jirovecii pneumonia; TB, tuberculosis. This is a cohort study examining outcomes of patients treated at the Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK, between 2010 and 2020. A comparator cohort of patients treated at our center between 2006 and 2009 was used to compare outcomes against the current regimen. All patients gave their consent for treatment and received standard care according to our accepted unit protocols. As this was a retrospective review, it met the criteria for a service evaluation study and hence did not require approval from a research ethics committee. Patients were followed up for a minimum of 1 year and up until their last clinical interaction before April 30, 2021. The diagnosis of AAV was based on either (i) the presence of circulating ANCA detected by indirect immunofluorescence or antigen-specific assay and/or (ii) biopsy-proven pauci-immune GN, and/or (iii) typical clinical features in cases where biopsy was contraindicated, in keeping with the Chapel Hill Consensus Nomenclature.13Jennette J.C. Falk R.J. Bacon P.A. et al.2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.Arthritis Rheum. 2013; 65: 1-11Crossref PubMed Scopus (3451) Google Scholar Patients with circulating anti–glomerular basement membrane antibodies were excluded. We included all patients who presented with life-threatening manifestations, defined as presentations with DAH and/or severe kidney injury (serum creatinine >500 μmol/L or the requirement for RRT within the first 48 hours). Patients were either assigned to the myeloperoxidase (MPO)–ANCA or 3 as by antigen-specific or indirect patients with biopsy-proven pauci-immune were ANCA by both indirect immunofluorescence and antigen-specific the of this these patients were assigned to either or according to their clinical with polyangiitis to microscopic polyangiitis and vasculitis to disease we used 3 of the Birmingham Vasculitis Activity Score R. D. et and of the Birmingham Vasculitis Activity Score (version Dis. PubMed Scopus Google Scholar At patients with in the presence of or kidney and disease were to have a of was defined as a of was by an in disease treatment and was as or using were by for and was defined at a of The GFR was estimated using the of in Renal A.S. et of in Renal A more to glomerular filtration rate from serum a new Med. PubMed Scopus Google Scholar was defined by an from kidney were according to the and using the Renal et of ANCA-associated glomerulonephritis.J Am Soc Nephrol. 2010; PubMed Scopus Google M. P. et and of a renal risk in ANCA-associated 2018; Full Text Full Text PDF PubMed Scopus Google Scholar included those to for i.v. treatment and as including The treatment (Table included a of low-dose i.v. cyclophosphamide, rituximab, and glucocorticoids were not and oral glucocorticoids were rapidly to a dose of within for Pneumocystis jirovecii ulcer disease, disease, and in patients from high-risk was as In patients with of B infection was to maintenance was with at 3 and was to for at or rituximab was used in patients who were of A comparator cohort of patients treated at our center between 2006 and 2009 was used to compare outcomes against the current regimen. patients met the criteria as the current study (i.e., severe kidney and/or and were treated with a combination of PEX, i.v. cyclophosphamide using a conventional oral versus Cyclophosphamide as therapy for ANCA-associated Vasculitis and R.J. D. R. et cyclophosphamide and in ANCA-associated J Am Soc Nephrol. 2013; PubMed Scopus Google Scholar We outcomes to those that be in or All were as and reported using and and between was by for and for continuous and were as and were by to follow-up were at last clinical and were for where and ANCA were at the of with cytotoxic or was using were and was using The features, and disease features of treated patients in patients presented with de disease of and was of patients with and All patients had of severe disease with median of all in and disease median disease included disease, and disease included disease, disease, and kidney kidney disease included disease, and at cytoplasm Birmingham Vasculitis Activity estimated glomerular filtration reported as or median disease included disease, and disease included disease, disease, and kidney disease included disease, and Open table in a new tab cytoplasm Birmingham Vasculitis Activity estimated glomerular filtration reported as or median creatinine and were μmol/L and 9 ml/min, patients required RRT at patients were with DAH. All had features in keeping with of had and of had or of that was with alveolar hemorrhage in all patients patients required or and a received membrane The median duration of total follow-up was 46 months. The median doses of rituximab, cyclophosphamide, and oral glucocorticoid in the first were 2, 3, and 2.6 g, to the in the M. Merkel P.A. Peh C.A. et al.Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis.N Engl J Med. 2020; 382: 622-631Crossref PubMed Scopus (179) Google methylprednisolone is not at our of 64 received at 1 dose before (median dose for This compares to 1 to 3 g received by patients enrolled in All patients received adjunctive PEX, with a median of at a dose of 60 ml/kg 4 per exchange. maintenance treatment was with of and with mycophenolate of or rituximab of in those who were patients did not maintenance of of kidney in disease or for infection The glucocorticoid taper was not the median time to a dose of oral was and of patients to low-dose glucocorticoids month At 60 patients achieved remission In keeping with this early were rapid in GFR serum and ANCA from 1 month All patients achieved and those by antigen-specific at presentation of rapidly of at a median time of 4 months. survival and kidney outcomes for the cohort at and and for kidney in In patients who required RRT at kidney in of within the first month of At of of these recovered patients were and remained free of In those presenting with serum creatinine >500 not dialysis, survival was of and of at and and kidney survival at and for patients of 64 of 64 of of 60 of 64 of 64 at presentation of of of of of of >500 RRT of of of of of of μmol/L plasma exchange for diffuse alveolar of of of of of of end-stage kidney renal replacement as of total for Patients plasma exchange for diffuse alveolar hemorrhage. Open table in a new tab end-stage kidney renal replacement as of total At and most patients had independent kidney of 60 and 46 of At last a total of of 64 patients had to of these patients were dialysis at presentation and did not the to at a median of and In patients not the median to at 3 rates during long-term follow-up were At and 36 of 60 of and of of respectively, were free from disease survival was associated with periods of ANCA and depletion (median time to was During total patients a at a median time of in those who did were more in patients with of in to of At time of first which 9 were and 4 were most patients had B of and all were before or at relapse; 4 patients were patient had a in the of both circulating ANCA and B All were treated with 3 patients with received a of low-dose cyclophosphamide in At 36 overall patient survival was of of during the first 3 of and of during total in were the most with of of the cohort at 1 infection The overall infection rate was 0.28 per year during total within the first and the infection rate to per year of infection before included and disease not dialysis or of at presentation were cases of B or progressive and in first 3 point, of dialysis with to early to vasculitis with significant to with and A to during study 1 (6) Pneumocystis disease Open table in a new tab disease patients kidney biopsy at presentation of was on 46 kidney biopsy biopsy was with vasculitis in a patient with clinical features with AAV, including DAH and for The most was of followed by of of and of the Renal biopsy was as low of 46 were as and of 46 were as In the overall both patients for risk of progression to and and for the and In those patients who presented with kidney and had a kidney biopsy patients with disease did not kidney during the first 4 of the rates of kidney were in those with and disease the patients with an were more independent kidney within the first 4 of with those as risk of all patients had <15 ml/min, this was by in both in those who recovered and those who did and the of in the biopsy patients treated at our center between 2006 and 2009 with a combination of PEX, i.v. cyclophosphamide using a conventional and glucocorticoids were used to compare outcomes against the current using the patients had features to the current cohort at median of and had DAH. patients required dialysis at of of recovered independent kidney by with 67% in the current During long-term the current regimen was associated with survival at 36 of in the historic with 29 of in the current This study for the use of combination induction therapy with rituximab and cyclophosphamide in AAV. In this of patients with and severe presentations of AAV, we rates of remission and from kidney with periods of We that low-dose cytotoxic may in to rapid and prolonged as by rates of ANCA after completion of induction therapy with low risk in M. M. et anti-neutrophil cytoplasm antibody at to maintenance therapy is associated with a reduced risk of Res 2017; PubMed Scopus Google M. et controlled trial of prolonged treatment in the remission of ANCA-associated Dis. 2017; PubMed Scopus Google and prolonged periods of The of rituximab and cyclophosphamide, with glucocorticoids, for remission induction in patients with kidney disease (serum was in the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis Merkel P.A. R. et al.Rituximab versus cyclophosphamide for ANCA-associated vasculitis.N Engl J Med. 2010; 363: PubMed Scopus Google Scholar recent from the trial suggest of these in most patients with more severe kidney M. Merkel P.A. Peh C.A. et al.Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis.N Engl J Med. 2020; 382: 622-631Crossref PubMed Scopus (179) Google Scholar However, the overall of patients treated with rituximab in the study was and in those treated with a glucocorticoid regimen in addition to rituximab, was a rates of and This as it may that cyclophosphamide is in this A recent retrospective cohort study the outcomes of patients with severe kidney disease in the study by and in rates of or after or induction from kidney in of M. et of rituximab and plasma exchange in antineutrophil cytoplasmic antibody-associated vasculitis with severe renal Am Soc Nephrol. 2020; PubMed Scopus Google Scholar the need for more treatment regimens in patients with kidney at We suggest that the addition of cyclophosphamide to rituximab may to a of and more rapid control of kidney and early kidney we rapid in and ANCA within the first month of treatment in our and and rates of kidney with published The may be during long-term survival in our was with historic treated with a conventional induction regimen at 3 We that survival in AAV has in recent M. P. et in anti-neutrophil cytoplasmic antibody (ANCA)-associated a follow-up Dial Transplant. 2013; PubMed Scopus Google Scholar and that than immunosuppressive including those to and to as membrane may for the outcomes in the current long-term follow-up of kidney outcomes that for ANCA-associated have to with severe we that the Renal Score those patients who recovered independent kidney by 4 as This that features may be used to patients to from and that their use be in treatment trials in the The use of combination regimens may infection in patients with severe disease who more to infection to disease, dialysis or the of kidney We that the cumulative dose of cyclophosphamide received in our cohort is than that in regimens 3 g in the Jayne D.R. et versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated a randomized Med. PubMed Scopus Google and that the overall of infection was to that reported in studies using or combination R.B. Tervaert J.W. Hauser T. et al.Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.N Engl J Med. 2010; 363: 211-220Crossref PubMed Scopus (1109) Google N. J. et infection in anti-neutrophil cytoplasmic antibody-associated from a 2020; PubMed Scopus Google Scholar these the need to infection risk in AAV with all current induction We that and a of disease were significant of early and studies of in those with risk for retrospective studies have that i.v. glucocorticoid use is associated with more in patients with AAV, in and those with severe disease D. P. et methylprednisolone for induction of remission in severe ANCA associated a retrospective cohort Nephrol. 2019; PubMed Scopus Google D. H. et and renal risk for early severe in patients with antineutrophil cytoplasmic autoantibody-associated a retrospective (Baltimore). 2020; PubMed Scopus (12) Google Scholar We that i.v. glucocorticoid use was low in our study (median dose for than the 1 to 3 g received in recent controlled studies, as Thus, the risk of combined cyclophosphamide and rituximab may be by the from the reduced glucocorticoid use that it in this The of adjunctive in this cohort be from that use of during not long-term kidney and patient However, the of patients with severe DAH in this study was and the of on kidney outcomes than a of combined kidney and patient and on from kidney in this study has not been In our we significant in between patients dialysis at and those presenting with serum creatinine >500 μmol/L not dialysis and and we it be to compare these in the is that the use of in our cohort may have glucocorticoid with use in the study, where it to i.v. and in to the study, where patients received both i.v. glucocorticoids and is that in our cohort with life-threatening disease, was from PEX, in addition to the immunosuppressive regimen. therapy has as an approach in and in the treatment of combination as and rituximab, in AAV the of rituximab and cyclophosphamide in randomized trials in the including those patients with life-threatening from and the All the of this were presented in at the of Kidney and the International Vasculitis and ANCA is by a for was by a was by a is by the and of Renal We from the Imperial with The and for their in our We that to the use of i.v. methylprednisolone in the Methylprednisolone versus plasma exchange and Plasma exchange and glucocorticoid in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS) studies, which in our We for the to compare the of patients in our cohort who received i.v. glucocorticoids in addition to plasma exchange (PEX) versus those who did not (Table 1). PDF the addition of high-dosage methylprednisolone to plasma exchange was more than plasma exchange in the treatment for severe antineutrophil cytoplasmic with the recent by et the of a combination regimen of plasma rituximab, low-dose i.v. cyclophosphamide, and oral glucocorticoids for the treatment of severe cytoplasmic vasculitis reported an overall patient survival of 85%, and 69% of patients remained free from end-stage kidney disease during long-term with a median duration of 46 which a of this regimen. PDF

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