key: cord-0690050-xh4c03ka
authors: Salas, Antonio; Kant, Sam; Floyd, Lauren; Kratky, Vojtěch; Brix, Silke R.; Prendecki, Maria; Schonermarck, Ulf; Scott, Jennifer; Saha, Manish; Gauckler, Philipp; Li, Tingting; Sharma, Purva D.; Ayoub, Isabelle; Morris, Adam D.; Dhaygude, Ajay P.; Hruskova, Zdenka; Tesar, Vladimir; McAdoo, Stephen P.; Little, Mark A.; Derebail, Vimal K.; Poulton, Caroline J.; Seo, Philip; Kronbichler, Andreas; Geetha, Duvuru
title: ANCA vasculitis induction management during the COVID-19 pandemic
date: 2021-08-19
journal: Kidney Int Rep
DOI: 10.1016/j.ekir.2021.08.009
sha: b52cf306068a8c94b0552b3654b4d835bdb58dc5
doc_id: 690050
cord_uid: xh4c03ka

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As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic evolved and became a global health threat, the safety of immunosuppression in antineutrophil cytoplasmic antibody associated vasculitis (AAV) became utmost important for clinicians and patients. While timely initiation of immunosuppressive therapy is critical to quell the acute inflammation and prevent AAV associated mortality and morbidity, concerns for increased susceptibility to COVID-19, delayed viral clearance and decreased humoral response to infection led to speculation about modification in induction therapy practices may be deployed by physicians caring for AAV patients. This international retrospective cohort study investigated the influence of the COVID-19 pandemic on AAV induction therapy and patient outcomes in different parts of the world by studying differences in treatment regimens in the, US, UK, and Europe.

Of the 191 patients, mean age was 65 (SD 14), 52% were female with majority (89%) being Caucasian. Kidney involvement was present in 155 (81%) patients and mean entry eGFR on was 34 (SD 31) ml/min/1.73 m 2 with 21% requiring dialysis at presentation. Baseline characteristics of patients are outlined in table 1.

With regards to induction immunosuppression, mean cumulative steroid dose for remission induction was 2962 mg (SD 1841) with the US having the highest average dose, which was 4153 mg (SD 2427) p<0.001. Prednisone regimen stratified by time course, center and region is presented in table 2. Forty-six patients (26%) in the whole cohort were off corticosteroids at 6 months, while 14 (36%) US patients, 16 (21%) UK patients, and 16 (26%) European patients were no longer given steroid treatment at 6 months (p=0.21).

Eighty-four patients (44%) received rituximab treatment without cyclophosphamide with the US having the highest proportion undergoing this treatment regimen (64% of patients; p=0.005). On the other hand, 49 (26%) patients were treated with cyclophosphamide without rituximab for induction treatment and Europe had the highest proportion of patients given cyclophosphamide alone (33%; p=0.037) [ Table 2 ].

The outcomes of remission induction therapy are depicted in Table 3 . At 6 months, 73 (92%) patients in the rituximab group, 42 (91%) patients in the cyclophosphamide group, and 39 (87%) patients who underwent combined therapy reached remission (p=0.564). Mean eGFR at 6 months was 43 (SD 29) ml/min/1.73 m 2 in the rituximab group, 33 (SD 24) ml/min/1.73 m 2 in the cyclophosphamide group and 47 (SD 36) ml/min/1.73 m 2 for those who received combination therapy (p=0.0659). Additionally, the rituximab, cyclophosphamide, and combination groups all had a median increase in GFR of 6 ml/min/1.73 m 2 over 6 months (p=0.68) ( Table 3 ; supplementary material). Nineteen patients (61%) out of the surviving 31 (two patients died) had kidney recovery at the end of the study after presenting with dialysis dependent kidney failure. Nineteen J o u r n a l P r e -p r o o f patients reach ESKD at the end of follow up with similar incidence across the different induction regimes.

Sixteen patients were diagnosed with COVID-19 during the induction period, with similar cyclophosphamide and rituximab exposure and half of these patients received combined therapy (table 4; supplementary material). The median interval from AAV diagnosis or relapse to COVID-19 infection was 33 (IQR 4-168) days. Patients who had COVID-19 infection had similar treatment regimens compared to patients who tested negative for SARS-CoV-2 (table 4) . Of the patients with COVID-19, four patients died of COVID-19, of which 3 (75%) had received combined rituximab and cyclophosphamide therapy while the other patient received cyclophosphamide alone. The median cumulative steroid induction dose for patients who died and had COVID-19 was 2423 (IQR 1210-5370) mg and the mean cumulative methylprednisolone dose for this group was 937.5 mg (SD 125). Of the COVID-19 patients, seven were hospitalized for infectious causes (one of which had cellulitis and another had bacteremia). Outcomes of patients diagnosed with COVID-19 are summarized in table 5 (supplementary material).

Differences in outcomes between the US, UK, and European cohorts, between with new and relapsing AAV and in treatment of patients with relapsing and new disease are summarized in Table 6 , 7 and 8 respectively (supplementary material).

This international multi-centered retrospective cohort study demonstrates that there was no deviation in the standard of care induction therapy of AAV during the pandemic and more importantly a less aggressive regimen was not utilized highlighting the importance of optimal vasculitis management. Both rituximab and cyclophosphamide induction regimens had similar infectious risk, remission rate, and kidney function outcomes in our study. This complements previous studies that suggest that adverse events, remission induction, and kidney function improvement are similar among both regimens. 1,2 Our data also shows that there were no differences in susceptibility to COVID-19 in our AAV cohort. Therefore, a change in induction regime may not be warranted and robust control of disease activity should continue to be prioritized in the current pandemic. This study additionally demonstrates significant center-based differences in induction treatment regimens and predominant use of rheumatoid arthritis (RA) dosing regimen for rituximab.

Interestingly, the rituximab group had the lowest mean cumulative steroids dose for induction and had the lowest proportion of patients that received pulse methylprednisolone therapy while the cyclophosphamide group had the highest proportion of patients given pulse methylprednisolone and had the highest mean cumulative steroid dose for induction. Notably, a reduced steroid exposure in rituximabtreated patients compared with cyclophosphamide-treated patients was also reported in the RAVE trial despite using the same glucocorticoid regime in both treatment arms. 1

This might reflect a higher confidence in the long acting effect of B cell depletion by the prescribing physician or a higher rate of true remission.

In our patients, there was a high proportion of patients still treated with glucocorticoids at the 6 month follow up, which is consistent with multiple centers having corticosteroid taper regimens extending past this time period. Additionally, this cohort was enriched with rituximab treated patients receiving 2 doses of 1000 mg given 2 weeks apart compared to the FDA approved regimen of 375 mg/m 2 once weekly for 4 weeks. This trend in dosing regimen likely evolved with the need to minimize exposure to SARS-CoV-2 virus in healthcare settings, although it is possible that some centers use this regimen as their standard of rituximab treatment for AAV induction. Use of PLEX therapy was low in our study population, which may be influenced by changes to practice patterns after the PEXIVAS study, which showed that PLEX therapy did not improve mortality or ESKD outcomes in patients with severe AAV. 3 There were multiple differences in AAV induction therapy practices among the US, UK, and Europe. Despite the UK having the highest proportion of patients presenting in AAV relapse, the US had the highest proportion of patients given rituximab treatment, which is consistent with recent AAV treatment trends in the US. 4 On the other hand, patients in the UK and Europe used cyclophosphamide therapy more than the US. The US had the highest corticosteroid use among all locations studied. A more widespread usage of the initial high dose intravenous steroid pulse in the US cohort resulted in the highest cumulative steroid dose for induction among all locations studied. Despite the difference in steroid dosing, no differences were observed in the daily steroid doses of patients at 16 week and 6-month intervals or in the proportion of patients off glucocorticoids at 6 months.

A high proportion of COVID-19 patients in this cohort were hospitalized for infection and died. This study was conducted prior to the RECOVERY trial, which showed favorable data about use of oral dexamethasone and tocilizumab for COVID-19 management, 5,6 and may help explain why the COVID-19 patients in our cohort had poor outcomes. Immunosuppressed patients with these updated therapies may have improved outcomes compared to our study.

Our study is subject to limitations inherent in a retrospective study. We were unable to assess long term kidney outcome and relapse due to short follow up period. Our analysis on COVID-19 susceptibility was limited by the lack of universal testing for SARS-CoV-2 infection. This is the first study evaluating AAV induction therapy patterns and outcomes during the COVID-19 pandemic highlighting the importance of optimal management of active vasculitis in times of the pandemic. Preliminary experience from case cohort studies highlights that immunosuppression may not confer the highest risk of COVID-19 vulnerability. [7] [8] [9] Therefore, it is that recommend standard immunotherapy be continued in AAV to minimize vasculitis related morbidity and mortality.

J o u r n a l P r e -p r o o f

Rituximab versus cyclophosphamide for ANCA-associated vasculitis. The New England journal of medicine

Rituximab versus cyclophosphamide in ANCAassociated renal vasculitis. The New England journal of medicine

Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis

ANCA-associated vasculitis management in the united states: Data from the rheumatology informatics system for effectiveness (RISE) registry

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial

Dexamethasone in hospitalized patients with covid-19. The New England journal of medicine

COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: A prospective cohort study

Factors associated with COVID-19-related death using OpenSAFELY

Results from the IRoc-GN international registry of patients with COVID-19 and glomerular disease suggest close monitoring