Intravenous pulse methylprednisolone (MP) is commonly included in the management of severe ANCA associated vasculitis (AAV) despite limited evidence of benefit. We aimed to evaluate outcomes in patients who had, or had not received MP, along with standard therapy for remission induction in severe AAV. We retrospectively studied 114 consecutive patients from five centres in Europe and the United States with a new diagnosis of severe AAV (creatinine > 500 μmol/L or dialysis dependency) and that received standard therapy (plasma exchange, cyclophosphamide and high-dose oral corticosteroids) for remission induction with or without pulse MP between 2000 and 2013. We evaluated survival, renal recovery, relapses, and adverse events over the first 12 months. Fifty-two patients received pulse MP in addition to standard therapy compared to 62 patients that did not. There was no difference in survival, renal recovery or relapses. Treatment with MP associated with higher risk of infection during the first 3 months (hazard ratio (HR) 2.7, 95%CI [1.4–5.3], p = 0.004) and higher incidence of diabetes (HR 6.33 [1.94–20.63], p = 0.002), after adjustment for confounding factors. The results of this study suggest that addition of pulse intravenous MP to standard therapy for remission induction in severe AAV may not confer clinical benefit and may be associated with more episodes of infection and higher incidence of diabetes.
Pregnancy in patients with anti-neutrophil cytoplasm antibody-associated vasculitis is reportedly associated with a high risk of fetal and maternal complications. Here we describe the outcome of pregnancies in patients with granulomatosis with polyangiitis and microscopic polyangiitis at five centers in the United Kingdom using a retrospective case review of all women who became pregnant following diagnosis. We report 15 pregnancies in 13 women resulting in 15 live births including one twin pregnancy and 13 singleton pregnancies. One patient had an unplanned pregnancy and a first trimester miscarriage while taking methotrexate. All other pregnancies were planned following a minimum of 6 months clinical remission. Eleven successful pregnancies were delivered vaginally at full term, whereas three were delivered by cesarean section. All infants were healthy with no neonatal complications on their initial health check within the first 24 h of delivery and no evidence of neonatal vasculitis. One relapse occurred during pregnancy and was successfully treated with an increased dose of azathioprine and corticosteroids, intravenous immunoglobulin, and plasma exchange therapy. One patient developed tracheal crusting and subglottic stenosis of infective etiology in the third trimester requiring tracheal debridement post delivery. No patient had a relapse in the first 12 months postpartum. Thus, successful pregnancy outcomes can occur following planned pregnancy in women in sustained remission on non-teratogenic therapies.
Programmed death-1 (PD-1), an inhibitory receptor up-regulated on activated T cells, has been shown to play a critical immunoregulatory role in peripheral tolerance, but its role in alloimmune responses is poorly understood. Using a novel alloreactive TCR-transgenic model system, we examined the functions of this pathway in the regulation of alloreactive CD4+ T cell responses in vivo. PD-L1, but not PD-1 or PD-L2, blockade accelerated MHC class II-mismatched skin graft (bm12 (I-Abm12) into B6 (I-Ab)) rejection in a similar manner to CTLA-4 blockade. In an adoptive transfer model system using the recently described anti-bm12 (ABM) TCR-transgenic mice directly reactive to I-Abm12, PD-1 and PD-L1 blockade enhanced T cell proliferation early in the immune response. In contrast, at a later time point preceding accelerated allograft rejection, only PD-L1 blockade enhanced T cell proliferation. In addition, PD-L1 blockade enhanced alloreactive Th1 cell differentiation. Apoptosis of alloantigen-specific T cells was inhibited significantly by PD-L1 but not PD-1 blockade, indicating that PD-1 may not be the receptor for the apoptotic effect of the PD-L1-signaling pathway. Interestingly, the effect of PD-L1 blockade was dependent on the presence of CD4+ CD25+ regulatory T cells in vivo. These data demonstrate a critical role for the PD-1 pathway, particularly PD-1/PD-L1 interactions, in the regulation of alloimmune responses in vivo.
Anti−glomerular basement membrane (anti-GBM) disease presents with rapidly progressive glomerulonephritis, often associated with alveolar hemorrhage and characterized histologically by crescentic glomerulonephritis. Typically, there is linear deposition of Ig along the glomerular basement membrane (GBM), which, in the majority of cases, is due to IgG autoantibodies directed against the noncollagenous domain of the α3 chain of type IV collagen (α3[IV]NC1).1
Clinical relapses are common in anti-neutrophil cytoplasm antibody (ANCA)–associated vasculitis, necessitating repeated treatment with immunosuppressive therapy, and increasing the risks of severe adverse events. Better understanding the basis of relapse would help stratify patients, testing the notion that more treatment may prevent development of relapse, whereas in those at low risk of disease flares, treatment minimization may be appropriate, reducing risks of adverse events, most notably infectious complications and drug toxicity. However, relapse can only occur following remission, and although defining clinical remission may seem straightforward, there is evidence in many remission patients of persistent inflammatory and immunological activity, at levels above those found in healthy individuals. This suggests that we may not truly be achieving disease remission in many patients and these persistent responses may set the patient up for subsequent disease flares. Understanding the underlying pathophysiological basis of disease activity and remission is paramount to help define better biomarkers of relapse, which should positively affect adverse events and patient outcomes. Clinical relapses are common in anti-neutrophil cytoplasm antibody (ANCA)–associated vasculitis, necessitating repeated treatment with immunosuppressive therapy, and increasing the risks of severe adverse events. Better understanding the basis of relapse would help stratify patients, testing the notion that more treatment may prevent development of relapse, whereas in those at low risk of disease flares, treatment minimization may be appropriate, reducing risks of adverse events, most notably infectious complications and drug toxicity. However, relapse can only occur following remission, and although defining clinical remission may seem straightforward, there is evidence in many remission patients of persistent inflammatory and immunological activity, at levels above those found in healthy individuals. This suggests that we may not truly be achieving disease remission in many patients and these persistent responses may set the patient up for subsequent disease flares. Understanding the underlying pathophysiological basis of disease activity and remission is paramount to help define better biomarkers of relapse, which should positively affect adverse events and patient outcomes. Relapsed. A deterioration in a patient's condition after a partial or apparently complete recovery; return of a disease, symptom, etc., after an interval of recovery.—Oxford English Dictionary ANCA-associated vasculitis, like many autoimmune diseases in which exposed autoantigens persist, follows a relapsing and remitting course, although the disease pattern for individual patients even with similar ANCA subtypes can be extremely variable. Certain susceptibility factors for relapse have been well established, such as proteinase-3–ANCA and clinical features of granulomatosis with polyangiitis; however, we have made few inroads into understanding what the pathophysiological drivers of relapse are, and why they are so different in patients with different ANCA subtypes. In part this is because, although overt disease flare may be clinically and immunologically obvious, subtle immune disease activity may be frequently missed. This subclinical inflammation brings into question what we mean by, and how we define, remission, which is generally based on clinical features, whereas more sensitive immunological or inflammatory phenotypes are not considered. We have introduced scoring systems, such as the Birmingham Vasculitis Activity Score and Birmingham Vasculitis Activity Score for Wegener's granulomatosis, which suggest that disease is in remission when the score is zero, but we cannot always easily differentiate active disease from damage, which means we may not score some features that may portend ongoing inflammation after certain time points. Persistent or mild hematuria, subtle elevations in creatinine, or some ear, nose, and throat symptoms may be related to scarring or active disease and may not be recorded as active or persistent disease in these scoring systems. This may be appropriate, as we now realize that it can take many months for these symptoms or parameters to normalize; however, it emphasises that we need more sensitive biomarkers to inform us of when disease is truly supressed or switched off. For relapse to occur, first there must be remission, and although we know when patients are overtly not in remission, because of ongoing signs and symptoms, it is fair to say we do not have robust definitions of when they really have achieved remission. Using an analogy of an iceberg to represent disease (Figure 1), there may be a large part of the iceberg that is not visible above the water surface, which could represent the subclinical inflammation defined by various biomarkers, which may persist as overt clinical disease, slowly declines, and patients achieve clinical remission. Some persistent inflammation may result in symptoms that could be interpreted as being due to disease or damage, such as persistent crusting or epistaxis in granulomatosis with polyangiitis, whereas in some cases persistent inflammation may produce no overt clinical signs at all. Conversely, there are some patients who have clearly switched their disease off, and using a variety of parameters show immunological “normality,” behaving like healthy individuals. How we measure and define remission will inform us of relapse. For the moment, we are still reliant on clinical parameters, and clear markers of active inflammation, such as elevated levels of C-reactive protein, fibrinogen, and platelets, that are inadequate for optimal customization of therapies. It has been a consistent finding from varied cohort studies and clinical trials that that being cytoplasmic-ANCA or proteinase-3–ANCA positive1Pagnoux C. Hogan S.L. Chin H. et al.Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts.Arthritis Rheum. 2008; 58: 2908-2918Crossref PubMed Scopus (194) Google Scholar,2Walsh M. Flossmann O. Berden A. et al.Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis.Arthritis Rheum. 2012; 64: 542-548Crossref PubMed Scopus (254) Google Scholar rather than perinuclear-ANCA or myeloperoxidase-ANCA positive was a significant risk for relapsing disease (Table 1). In keeping with the immunological phenotype, patients with granulomatosis with polyangiitis have more clinical relapses than patients with microscopic polyangiitis, as do those with involvement of the lungs, upper airways,1Pagnoux C. Hogan S.L. Chin H. et al.Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts.Arthritis Rheum. 2008; 58: 2908-2918Crossref PubMed Scopus (194) Google Scholar or cardiovascular system.2Walsh M. Flossmann O. Berden A. et al.Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis.Arthritis Rheum. 2012; 64: 542-548Crossref PubMed Scopus (254) Google Scholar,3Pierrot-Deseilligny Despujol C. Pouchot J. Pagnoux C. et al.Predictors at diagnosis of a first Wegener's granulomatosis relapse after obtaining complete remission.Rheumatology (Oxford). 2010; 49: 2181-2190Crossref PubMed Scopus (55) Google Scholar In addition, higher levels of renal function2Walsh M. Flossmann O. Berden A. et al.Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis.Arthritis Rheum. 2012; 64: 542-548Crossref PubMed Scopus (254) Google Scholar and carriage of nasal Staphylococcus aureus4Stegeman C.A. Tervaert J.W. Sluiter W.J. et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Scopus (673) Google Scholar appear to confer greater relapse risk, and this is true in both European and Chinese populations.3Pierrot-Deseilligny Despujol C. Pouchot J. Pagnoux C. et al.Predictors at diagnosis of a first Wegener's granulomatosis relapse after obtaining complete remission.Rheumatology (Oxford). 2010; 49: 2181-2190Crossref PubMed Scopus (55) Google Scholar,5Li Z.Y. Chang D.Y. Zhao M.H. Chen M. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated vasculitis: a study of 439 cases in a single Chinese center.Arthritis Rheumatol. 2014; 66: 1920-1926Crossref PubMed Scopus (44) Google Scholar In some cohort studies, persistent ANCA positivity at the time of switching from induction to maintenance therapy is associated with an increased risk of future relapse,6Morgan M.D. Szeto M. Walsh M. et al.Negative anti-neutrophil cytoplasm antibody at switch to maintenance therapy is associated with a reduced risk of relapse.Arthritis Res Ther. 2017; 19: 129Crossref PubMed Scopus (31) Google Scholar whereas previous relapses are themselves risk factors for subsequent relapses. Disappointingly, apart from some histological features (including proportion of sclerosed glomeruli and lack of interstitial infiltrates),7Goceroglu A. Berden A.E. Fiocco M. et al.ANCA-associated glomerulonephritis: risk factors for renal relapse.PLoS One. 2016; 11e0165402Crossref PubMed Scopus (19) Google Scholar there are no clear, clinically useful, predictors for renal relapse, which is associated with progression to end-stage renal disease. Importantly, rates of renal relapse, unlike other outcomes in ANCA-associated vasculitis, have remained relatively constant.8Rhee R.L. Hogan S.L. Poulton C.J. et al.Trends in long-term outcomes among patients with antineutrophil cytoplasmic antibody-associated vasculitis with renal disease.Arthritis Rheumatol. 2016; 68: 1711-1720Crossref PubMed Scopus (71) Google Scholar,9Wester Trejo M.A.C. Flossmann O. Westman K.W. et al.Renal relapse in antineutrophil cytoplasmic autoantibody-associated vasculitis: unpredictable, but predictive of renal outcome.Rheumatology (Oxford). 2019; 58: 103-109Crossref PubMed Scopus (12) Google Scholar Interestingly, progression to end-stage regnal disease occurs more frequently without overt renal relapses, which may highlight our inadequacies in diagnosing ongoing renal inflammation that may underlie some of what we term chronic kidney disease progression in patients with ANCA-associated glomerulonephritis.7Goceroglu A. Berden A.E. Fiocco M. et al.ANCA-associated glomerulonephritis: risk factors for renal relapse.PLoS One. 2016; 11e0165402Crossref PubMed Scopus (19) Google Scholar Supporting the idea that persistent inflammation promotes some of the progression are data from the Chronic Renal Insufficiency Cohort (CRIC) study that demonstrate more rapid progression of chronic kidney disease (of various causes) in patients with markers of inflammation, such as elevated levels of circulating proinflammatory cytokines (tumor necrosis factor-α) and fibrinogen and lower levels of albumin.10Amdur R.L. Feldman H.I. Gupta J. et al.Inflammation and progression of CKD: the CRIC study.Clin J Am Soc Nephrol. 2016; 11: 1546-1556Crossref PubMed Scopus (223) Google ScholarTable 1Recognized risk factors for relapse in ANCA-associated vasculitisDisease parametersManagement parameters1. PR3-ANCA1. Early drug withdrawal at 1 year2. GPA disease2. Induction therapy type; see Table 23. Higher presenting eGFR3. Maintenance therapy type; see Table 24. Staphylococcus aureus nasal carriage4. Antibiotic prophylaxis with co-trimoxazole5. ANCA positivity at time of completion of induction therapy6. Previous relapsesANCA, anti-neutrophil cytoplasm antibody; eGFR, estimated glomerular filtration rate; GPA, granulomatosis with polyangiitis; PR3, proteinase 3. Open table in a new tab ANCA, anti-neutrophil cytoplasm antibody; eGFR, estimated glomerular filtration rate; GPA, granulomatosis with polyangiitis; PR3, proteinase 3. Modern induction regimens are generally very effective at producing disease remission, but which drug is used and which maintenance regimens patients are switched to, are more variable in the ability to maintain it. This tells us that there may be different aspects of the immune response that are regulated by particular drugs, or they may do so more or less effectively. Various cohort studies and long-term follow-up of international trials have demonstrated relapse rates that vary between 21% and 89% at 5 years, depending on the induction and maintenance regimens that were used (Table 211Jayne D. Rasmussen N. Andrassy K. et al.A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.N Engl J Med. 2003; 349: 36-44Crossref PubMed Scopus (1174) Google Scholar, 12De Groot K. Rasmussen N. Bacon P.A. et al.Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis.Arthritis Rheum. 2005; 52: 2461-2469Crossref PubMed Scopus (651) Google Scholar, 13de Groot K. Harper L. Jayne D.R. 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, 14Pagnoux C. Mahr A. Hamidou M.A. et al.Azathioprine or methotrexate maintenance for ANCA-associated vasculitis.N Engl J Med. 2008; 359: 2790-2803Crossref PubMed Scopus (518) Google Scholar, 15Hiemstra T.F. Walsh M. Mahr A. et al.Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.JAMA. 2010; 304: 2381-2388Crossref PubMed Scopus (445) Google Scholar, 16Guillevin L. Pagnoux C. Karras A. et al.Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.N Engl J Med. 2014; 371: 1771-1780Crossref PubMed Scopus (645) Google Scholar, 17Stone 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, 18Jones 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 (1195) Google Scholar). More recent trials have suggested that rates can be brought down to as low as 5% at 2 years with use of rituximab,16Guillevin L. Pagnoux C. Karras A. et al.Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.N Engl J Med. 2014; 371: 1771-1780Crossref PubMed Scopus (645) Google Scholar which appears to be a significant improvement compared with previous rates (Table 2).Table 2Relapse rates in recent ANCA-associated vasculitis trialsTrialComparedResultsRates of relapseReferenceCYCAZAREMCYP vs. CYP/AZASame relapse15.5% vs. 13.7% at 1.5 yr,52% vs. 36% at 8.5 yr11Jayne D. Rasmussen N. Andrassy K. et al.A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.N Engl J Med. 2003; 349: 36-44Crossref PubMed Scopus (1174) Google ScholarNORAMMTX vs. CYPGreater relapse MTX89% vs. 81% at 5 yr12De Groot K. Rasmussen N. Bacon P.A. et al.Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis.Arthritis Rheum. 2005; 52: 2461-2469Crossref PubMed Scopus (651) Google ScholarCYCLOPSi.v. vs. ORAL CYPGreater relapse with i.v. CYP39.5% vs. 20.8% at 5 yr13de Groot K. Harper L. Jayne D.R. 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 ScholarWEGENTAZA vs. MTXSame relapse36% vs. 33% at 2 yr14Pagnoux C. Mahr A. Hamidou M.A. et al.Azathioprine or methotrexate maintenance for ANCA-associated vasculitis.N Engl J Med. 2008; 359: 2790-2803Crossref PubMed Scopus (518) Google ScholarIMPROVEAZA vs. MMFGreater relapse with MMF37.5% vs. 55.2% at 3 yr15Hiemstra T.F. Walsh M. Mahr A. et al.Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.JAMA. 2010; 304: 2381-2388Crossref PubMed Scopus (445) Google ScholarMAINRITSANAZA vs. RTXGreater relapse with AZA29% vs. 5% at 28 mo16Guillevin L. Pagnoux C. Karras A. et al.Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.N Engl J Med. 2014; 371: 1771-1780Crossref PubMed Scopus (645) Google ScholarRAVERTX vs. CYP/AZASame relapse32% vs. 29% at 18 mo17Stone 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 ScholarRITUXVASRTX/CYP vs. CYP/AZASame relapse42% vs. 36% at 2 yr18Jones 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 (1195) Google ScholarAZA, azathioprine; CYP, cyclophosphamide; MMF, mycophenolate mofetil; MTX, methotrexate; RTX, rituximab.Trials in bold show significant benefit of one drug versus the other. Open table in a new tab AZA, azathioprine; CYP, cyclophosphamide; MMF, mycophenolate mofetil; MTX, methotrexate; RTX, rituximab. Trials in bold show significant benefit of one drug versus the other. Induction with either oral cyclophosphamide or rituximab (and glucocorticoids) results in similar relapse rates, but these are greater if intravenous pulsed cyclophosphamide,13de Groot K. Harper L. Jayne D.R. 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 or methotrexate,12De Groot K. Rasmussen N. Bacon P.A. et al.Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis.Arthritis Rheum. 2005; 52: 2461-2469Crossref PubMed Scopus (651) Google Scholar are used compared with oral cyclophosphamide, while pulsed cyclophosphamide results in fewer relapses than mycophenolate mofetil induction.19Jones R.B. Hiemstra T.F. Ballarin J. et al.Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial.Ann Rheum Dis. 2019; 78: 399-405Crossref PubMed Scopus (112) Google Scholar However, in addition to which drug is used, the duration of treatment is critical. For example, in the NORAM trial,12De Groot K. Rasmussen N. Bacon P.A. et al.Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis.Arthritis Rheum. 2005; 52: 2461-2469Crossref PubMed Scopus (651) Google Scholar treatment with either cyclophosphamide or methotrexate was equally effective at inducing remission; however, after 1 year of treatment, cessation of drug was accompanied by significantly higher relapse rate in patients treated with methotrexate. Similarly, maintenance therapy with azathioprine is associated with less risk of early relapse than use of mycophenolate,15Hiemstra T.F. Walsh M. Mahr A. et al.Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.JAMA. 2010; 304: 2381-2388Crossref PubMed Scopus (445) Google Scholar whereas rituximab maintenance was more effective at preventing relapse than azathioprine.16Guillevin L. Pagnoux C. Karras A. et al.Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.N Engl J Med. 2014; 371: 1771-1780Crossref PubMed Scopus (645) Google Scholar We have not understood what underlies these differences, and uncovering pathways that are variably effected by these various drugs may give us a clue as to what may provoke relapse. In addition, it is unclear how particular maintenance therapy prevents relapse, as there are mixed data suggesting that shorter or longer duration of therapy may be associated with increased or no difference in rates of relapse.20de Joode A.A.E. Sanders J.S.F. Puechal X. et al.Long term azathioprine maintenance therapy in ANCA-associated vasculitis: combined results of long-term follow-up data.Rheumatology (Oxford). 2017; 56: 1894-1901Crossref PubMed Scopus (30) Google Scholar, 21Sanders J.S. de Joode A.A. DeSevaux R.G. et al.Extended versus standard azathioprine maintenance therapy in newly diagnosed proteinase-3 anti-neutrophil cytoplasmic antibody-associated vasculitis patients who remain cytoplasmic anti-neutrophil cytoplasmic antibody-positive after induction of remission: a randomized clinical trial.Nephrol Dial Transplant. 2016; 31: 1453-1459PubMed Google Scholar, 22Karras A. Pagnoux C. Haubitz M. et al.Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis.Ann Rheum Dis. 2017; 76: 1662-1668Crossref PubMed Scopus (113) Google Scholar ANCA has been proposed as a marker of impending disease relapse since the early days of its introduction as a clinical test.23Tervaert J.W. Huitema M.G. Hene R.J. et al.Prevention of relapses in Wegener's granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre.Lancet. 1990; 336: 709-711Abstract PubMed Scopus (420) Google Scholar It was shown to be of some value in a single cohort study of patients with renal disease, with an ANCA increase (of more than 200% in the prior 3 months by solid phase assay) giving a hazard ratio of more than 11 for subsequent relapse in the next 18 months,24Kemna M.J. Damoiseaux J. Austen J. et al.ANCA as a predictor of relapse: useful in patients with renal involvement but not in patients with nonrenal disease.J Am Soc Nephrol. 2015; 26: 537-542Crossref PubMed Scopus (128) Google Scholar but was less predictive in those with nonrenal disease. Persistent ANCA positivity or development of positivity following a negative test showed only modest predictive power in a recent meta-analysis, with the caveat that this contained heterogeneous studies with variable testing strategies.25Tomasson G. Grayson P.C. Mahr A.D. et al.Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis—a meta-analysis.Rheumatology (Oxford). 2012; 51: 100-109Crossref PubMed Scopus (234) Google Scholar However, using the RAVE dataset, increase titer (doubling of value or reaching an absolute level if previously negative) of proteinase-3–ANCA, by enzyme-linked immunosorbent assay, was clearly associated with subsequent disease flare, but only in those treated with rituximab, with a hazard ratio of 7.9 in those with kidney involvement. There were additional differences in the strength of association depending on the type of enzyme-linked immunosorbent assay used.26Fussner L.A. Hummel A.M. Schroeder D.R. et al.Factors determining the clinical utility of serial measurements of antineutrophil cytoplasmic antibodies targeting proteinase 3.Arthritis Rheumatol. 2016; 68: 1700-1710Crossref PubMed Scopus (96) Google Scholar In addition, in a prospective Japanese cohort, reappearance of myeloperoxidase-ANCA had a significant association with subsequent relapse, with an odds ratio of 26 (95% confidence interval, 8.2–101.0), whereas ANCA persistence was not associated with higher rates of relapse.27Watanabe H. Sada K.E. Matsumoto Y. et al.Association between reappearance of myeloperoxidase-antineutrophil cytoplasmic antibody and relapse in antineutrophil cytoplasmic antibody-associated vasculitis: subgroup analysis of nationwide prospective cohort studies.Arthritis Rheumatol. 2018; 70: 1626-1633Crossref PubMed Scopus (22) Google Scholar Differences in myeloperoxidase-ANCA epitope specificity have been reported between acute disease and remission, suggesting there may be differences in antibody pathogenicity that could potentially explain ANCA persistence and clinical disease remission in some patients.28Roth A.J. Ooi J.D. Hess J.J. et al.Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis.J Clin Invest. 2013; 123: 1773-1783Crossref PubMed Scopus (184) Google Scholar,29Free ME, Stember KG, Hess JJ, et al. Restricted myeloperoxidase epitopes drive the adaptive immune response in MPO-ANCA vasculitis [e-pub ahead of print]. J Autoimmun. https://doi.org/10.1016/j.jaut.2019.102306. Accessed November 24, 2019.Google Scholar Standard ANCA measurements during remission remain a feature of clinical practice for many physicians and rising titers may warrant more careful follow-up, but it remains controversial whether that should result in immediate change of therapy. It is clear that many inflammatory pathways are engaged at the time of disease activity and relapse, and some of these never return to normality (seen in healthy controls) during remission,30Nogueira E. Hamour S. Sawant D. et al.Serum IL-17 and IL-23 levels and autoantigen-specific Th17 cells are elevated in patients with ANCA-associated vasculitis.Nephrol Dial Transplant. 2010; 25: 2209-2217Crossref PubMed Scopus (182) Google Scholar,31Sanders J.S. Huitma M.G. Kallenberg C.G. Stegeman C.A. Plasma levels of soluble interleukin 2 receptor, soluble CD30, interleukin 10 and B cell activator of the tumour necrosis factor family during follow-up in vasculitis associated with proteinase 3-antineutrophil cytoplasmic antibodies: associations with disease activity and relapse.Ann Rheum Dis. 2006; 65: 1484-1489Crossref PubMed Scopus (51) Google Scholar suggesting that they may be the subclinical factors driving relapse. Therefore, either there is a baseline abnormality in these pathways in patients compared with healthy individuals or the immunological pathways may remain turned on at lower levels without inducing overt disease. In part, our inability to predict relapse comes from the reliance on biomarkers that are poor at representing the subclinical inflammation that occurs (Figure 1), such as creatinine, proteinuria, and hematuria in patients with renal disease. An ideal biomarker to predict relapse in the near future would likely inform of how therapy may be tailored for the individual, minimizing exposure in those less likely to relapse and maintaining higher levels of therapy in those who have greater likelihood of disease flare (although we also need to prove that more treatment will prevent relapse). Optimally, this would be used at the time of disease presentation, during induction therapy or soon after, before deciding on maintenance therapy. Some markers have shown such associations, with variable positive predictive values in cohort studies, but the time lag to relapse may be protracted, meaning that augmented immunosuppression may be delivered to a significant number of individuals for a long period of time, increasing potential adverse events. Many other biomarkers, including circulating levels of leukocyte subsets (such as B- or T-lymphocyte subsets),32Morgan M.D. Day C.J. Piper K.P. et al.Patients with Wegener's granulomatosis demonstrate a relative deficiency and functional impairment of T-regulatory cells.Immunology. 2010; 130: 64-73Crossref PubMed Scopus (97) Google Scholar,33Bunch D.O. McGregor J.G. Khandoobhai N.B. et al.Decreased CD5(+) B cells in active ANCA vasculitis and relapse after rituximab.Clin J Am Soc Nephrol. 2013; 8: 382-391Crossref PubMed Scopus (73) Google Scholar urinary lymphocytes, or urinary leukocyte proteins34Abdulahad W.H. Kallenberg C.G. Limburg P.C. Stegeman C.A. Urinary CD4+ effector memory T cells reflect renal disease activity in antineutrophil cytoplasmic antibody-associated vasculitis.Arthritis Rheum. 2009; 60: 2830-2838Crossref PubMed Scopus (55) Google Scholar, 35de Souza A.W. Abdulahad W.H. Sosicka P. et al.Are urinary levels of high mobility group box 1 markers of active nephritis in anti-neutrophil cytoplasmic antibody-associated vasculitis?.Clin Exp Immunol. 2014; 178: 270-278Crossref PubMed Scopus (16) Google Scholar, 36O'Reilly V.P. Wong L. Kennedy C. et al.Urinary soluble CD163 in active renal vasculitis.J Am Soc Nephrol. 2016; 27: 2906-2916Crossref PubMed Scopus (81) Google Scholar, 37Tam F.W. Sanders J.S. George A. et al.Urinary monocyte chemoattractant protein-1 (MCP-1) is a marker of active renal vasculitis.Nephrol Dial Transplant. 2004; 19: 2761-2768Crossref PubMed Scopus (86) Google Scholar have been shown to be associated with disease activity, but none have validated as robust markers of subsequent relapse. The most promising biomarkers have been a CD8 T-cell subset that in a single-center study showed a strong association with subsequent relapse in patients with ANCA-associated vasculitis or systemic lupus erythematosus, which requires prospective validation.38McKinney E.F. Lyons P.A. Carr E.J. et al.A CD8+ T cell transcription signature predicts prognosis in autoimmune disease.Nat Med. 2010; 16 (1p following 91): 586-591Crossref PubMed Scopus (283) Google Scholar Another was changes in serum calprotectin levels, which increased while on therapy between baseline and month 3 or 6, in samples from the RAVE trial, again only in those treated with rituximab (like the predictive ability of proteinase-3–ANCA).39Pepper R.J. Draibe J.B. Caplin B. et al.Association of serum calprotectin (S100A8/A9) level with disease relapse in proteinase 3-antineutrophil cytoplasmic antibody-associated vasculitis.Arthritis Rheumatol. 2017; 69: 185-193Crossref PubMed Scopus (37) Google Scholar This suggests that differences exist in suppression of various inflammatory pathways when using different induction regimens, despite similar clinical remission rates, highlighting again that clinical remission is not telling us everything about underlying disease pathway suppression. Perhaps unsurprisingly, since the change in calprotectin was not predictive of relapse in cyclophosphamide-treated patients from RAVE, no association with relapse was found using samples from the MYCYC (mycophenolate vs cyclophosphamide) trial (unpublished data). These data suggest that other biomarkers or combinations of biomarkers could be found that should allow us to predict future disease relapse. Finally, there are those patients demonstrating prolonged disease-free remission40Hogan S.L. Nachman P.H. Poulton C.J. et al.Understanding long-term remission off therapy in antineutrophil cytoplasmic antibody-associated vasculitis.Kidney Int Rep. 2019; 4: 551-560Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar who have become ANCA negative and remain off all immunotherapy, including glucocorticoids, who may truly have switched off all of the subclinical inflammatory and immunological pathways, with some evidence that some of their regulatory cell subsets are numerically restored to levels found in healthy individuals (Oates T, Flores-Barros F, Todd SK, et al. Restablishment of immune tolerance in ANCA-associated vasculitis: a cohort with both sustained undetectable antibody, and disease free remission [abstract]. J Am Soc Nephrol. 2016;27:282). This group of patients may provide some clues as to what pathways underpin the subclinical inflammation and predisposition to relapse. One issue that is not discussed in studies comparing i.v. and oral therapies is compliance with the oral regimen, which can be suboptimal, with rates of noncompliance in many chronic rheumatological diseases estimated at more than 50% and as high as 82%.41Campbell N.K.J. Saadeldin K. De Vera M.A. The duality of economic issues with medication non-adherence in patients with inflammatory arthritis.Curr Rheumatol Rep. 2017; 19: 66Crossref PubMed Scopus (6) Google Scholar Although specific data for ANCA-associated vasculitis are lacking, this may be an issue especially in maintenance studies. Assessment of compliance through drug monitoring where possible may help in this regard. In addition, it is worth considering that unblinded trials of therapy withdrawal may be hindered by the risk of bias in defining a clinical event as a disease relapse if it is known that the patient is not on treatment, rather than a transient infection, for example. Future studies defining optimal regimens and duration of treatments should consider these issues, by potentially blinding physicians to treatments, using hard (inflammatory or immunological) endpoints, and making attempts at confirming compliance. We still rely on clinical definitions of remission and these are not clear-cut or uniform. We need better, more granular inflammatory and immunological profiles to really understand disease states. These should provide better markers of disease quiescence, activity, and potentially markers that can predict short- or long-term relapse. Only then will we be able to truly customize therapy for individual patients, minimizing risks of adverse events by appropriately reducing therapies in some, and reducing risks of relapse in others by appropriately augmenting therapies. The author declared no competing interests.
Crescentic glomerulonephritis (CGN), which frequently results in acute and chronic kidney disease, is characterized by and dependent on glomerular infiltration by macrophages. The mannose receptor (MR) is a pattern recognition receptor implicated in the uptake of endogenous and microbial ligands by macrophages, mesangial cells (MCs), and selected endothelial cells. It is upregulated on alternatively activated macrophages (i.e., macrophages associated with tissue repair and humoral immunity) and involved in antigen presentation to T cells. We used the mouse model of nephrotoxic nephritis to investigate the role of MR in CGN. Our results demonstrate what we believe to be a novel role for MR in the promotion of CGN that is independent of adaptive immune responses. MR-deficient (Mr-/-) mice were protected from CGN despite generating humoral and T cell responses similar to those of WT mice, but they demonstrated diminished macrophage and MC Fc receptor-mediated (FcR-mediated) functions, including phagocytosis and Fc-mediated oxygen burst activity. Mr-/- MCs demonstrated augmented apoptosis compared with WT cells, and this was associated with diminished Akt phosphorylation. Macrophage interaction with apoptotic MCs induced a noninflammatory phenotype that was more marked in Mr-/- macrophages than in WT macrophages. Our results demonstrate that MR augments Fc-mediated function and promotes MC survival. We suggest that targeting MR may provide an alternative therapeutic approach in CGN while minimizing the impact on adaptive immune responses, which are affected by conventional immunosuppressive approaches.
EBPb-/-chimeric mice, respectively.WT, C/EBPbþ/þ and C/EBPb-/chimeric mice developed glomerular necrosis and crescent formation.In contrast, CCR2-/-chimeric mice did not develop such renal damage.Erythrocyturia and albuminuria were also significantly reduced in CCR2-/-compared to WT chimeric mice.Flow cytometry showed a significant reduced renal infiltration of CM and NCM in CCR2-/-and C/EBPb-/-, respectively.In contrast, neutrophils, macrophages, and dendritic cell infiltration remained similar in all groups.Conclusion: Our findings provide novel experimental evidence that classical monocytes are important contributors of kidney damage in ANCA-mediated NCGN.The molecular mechanisms by which these cells promote kidney damage remain to be clarified.
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