Negative anti-neutrophil cytoplasm antibody at switch to maintenance therapy is associated with a reduced risk of relapse

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are potentially life-threatening inflammatory diseases. Whereas historically they were almost uniformly fatal, 5-year survival is now 78% but is often characterised by frequent relapses which are associated with significant morbidity and mortality [1‐5].

Previous studies have identified several factors associated with an increased risk of relapse including the presence of circulating proteinase 3 (PR3)-specific, as opposed to myeloperoxidase (MPO)-specific, anti-neutrophil cytoplasm antibodies (ANCA) at the time of disease diagnosis [6, 7]. The role of ANCA testing after diagnosis in predicting relapse has been the subject of many previous studies, although a recent meta-analysis concluded that persistence or a rise in ANCA titre (irrespective of specificity) during remission was only modestly predictive of relapse [8].

Previous studies suggested that the persistence of PR3-ANCA, but not MPO-ANCA, at the time of discontinuing cyclophosphamide and switching to maintenance therapy is associated with an increased risk of relapse [7, 9]. We used long-term follow-up data from two of the previous European Vasculitis Study Group (EUVAS) clinical trials, CYCLOPS and IMPROVE, to identify whether persistent ANCA positivity at the time of discontinuing cyclophosphamide and switching to maintenance therapy is associated with an increased risk of relapse in patients with moderate-to-severe ANCA-associated vasculitis (AAV) treated with cyclophosphamide as initial remission induction therapy [10, 11].

Previous studies have consistently demonstrated a higher risk of relapse for patients with PR3-ANCA (or cytoplasmic ANCA (cANCA)) at diagnosis compared to MPO-ANCA (or perinuclear ANCA) [17, 18, 20‐22]. In this study we addressed the issue of whether persistent ANCA at the time of switching to maintenance therapy was associated with an increased risk of relapse. We demonstrated that persistent ANCA at the switch to maintenance therapy is associated with an increased risk of relapse. In multivariable analysis, this association remained significant after adjusting for initial cyclophosphamide therapy regimen, maintenance therapy, age, and renal function. When we compared two multivariable models of the risk of relapse, the model including ANCA status at the time of switching to maintenance therapy gave a better fit to the observed risk of relapse than the model not including ANCA status at the time of switching to maintenance therapy.

The few studies that have previously examined this issue were limited by smaller sample size and analyses that were not adjusted for other known risk factors for relapse. These studies suggested that persistent cANCA by indirect immunofluorescence (IIF) was associated with an increased risk of relapse compared to patients in whom ANCA re-occurred following the switch to maintenance therapy or who were persistently negative in remission [7, 23]. One recent underpowered retrospective study compared the relapse rate of patients who were cANCA-positive or cANCA-negative at the time of remission and found no significant difference in relapse risk [24]. The significance of persistent MPO-ANCA at the time of switch to maintenance therapy was investigated in 62 Japanese patients with MPA and was not found to be associated with an increased risk of relapse, although several studies have reported an increased risk of relapse associated with an increase in MPO-ANCA titre once in remission [9, 25]. Rituximab is now increasingly being used for both remission induction and maintenance in AAV. Although several trials have reported on re-occurrence of ANCA after initial remission induction as a risk factor for relapse, none have reported on the ANCA status at the time of starting maintenance therapy as a risk factor for relapse [26‐28]. We tested the overall effect of remaining ANCA-positive at switching to maintenance therapy and also looked for evidence of an interaction between ANCA specificity and ANCA status at switching. There was no evidence of an interaction between these two variables, suggesting that the increased risk of relapse observed in patients remaining ANCA-positive was true for both MPO-ANCA- and PR3-ANCA-positive patients (Fig. 1).

Several factors that are recorded during routine clinical practice have now been identified that associate with an increased risk of relapse in patients with AAV: PR3-ANCA at diagnosis, persistent ANCA at switch to maintenance therapy, better renal function, younger age, pulsed cyclophosphamide for remission induction therapy, MMF for maintenance therapy, corticosteroid withdrawal, and cardiovascular system involvement [11, 12, 17, 20, 29]. Currently there is no clear evidence base to support decision making when considering maintenance or discontinuation of immunosuppression once a patient has been in remission for a period of time, although a recent meta-analysis suggested that patients should receive at least 18 months of corticosteroids to reduce the risk of subsequent relapse [29]. This study provides additional clinical information that can inform the discussion with an individual patient about the risk of relapse when planning maintenance immunosuppression therapy, although it is not possible to conclusively identify those patients who will or will not subsequently relapse—only those with a greater or lesser risk of relapse.

It is interesting to note that the patients who remained ANCA-positive at switching to maintenance therapy took longer to achieve remission than the patients who had become ANCA-negative. In the absence of hard objective measures of disease activity for AAV it is not possible to determine whether this is a real association or whether, because the physicians managing patients in the original trials were not blinded to treatment or ANCA status, knowledge of these factors influenced a physician’s judgement as to when patients entered remission and were switched to maintenance therapy. The same factors could also potentially influence the physician’s judgement as to whether symptoms represented relapse.

Patients in the CYCLOPS trial received cyclophosphamide for a longer period than the patients in the IMPROVE trial, and several CYCLOPS patients who were ANCA-positive at remission became ANCA-negative by the time of switching to maintenance therapy. Due to the small numbers of patients affected it is not possible to determine whether the additional cyclophosphamide received had a significant effect on the risk of relapse.

We are not able to determine from this study the role that ANCA plays in the development of relapse. We do not know how many of the patients who subsequently relapsed remained persistently ANCA-positive and how many of the patients who relapsed were ANCA-positive at the time of relapse. It is interesting to speculate whether ANCA positivity at the time of switching to maintenance therapy indicates a direct pathogenic role for ANCA in the re-occurrence of disease activity or whether it is a biomarker for continued lack of tolerance against the autoantigens and immunological resistance to treatment.

This study is limited in that the data are derived from two clinical trials. These studies were not designed to investigate whether remaining ANCA-positive at time of disease remission increases the risk of disease relapse. We also do not have data on how long the patients in this cohort remained on maintenance immunosuppressive therapy nor can we investigate the effect of cumulative immunosuppression and corticosteroids on relapse risk. However, it provides additional evidence that allows better relapse-risk assessment for the individual patient. It is larger than previous studies which have also suggested that ANCA positivity at the time of remission increases relapse risk and has demonstrated that this is true in multivariable analysis.

It is also important to point out that patients included in this study all received cyclophosphamide induction therapy and all but four received azathioprine or MMF maintenance therapy; thus, these results may not be applicable to patients who have received rituximab or additional plasma exchange as part of their remission induction regime.

The findings of this study provide useful information for the clinician to help stratify patients for their future risk of relapse. Further work is needed in understanding why persistent ANCA at the time of switching is associated with an increased risk of relapse and whether more detailed immunophenotyping of these patients may reveal new therapeutic targets and improved understanding of the mechanisms of AAV disease. In future this may allow us to develop trials specifically targeting new or additional therapy at patients at high risk of relapse to improve outcomes.