key: cord-0734225-5eyz2ypq
authors: Bruchfeld, Annette; Kronbichler, Andreas; Alberici, Federico; Fervenza, Fernando C; Jayne, David R W; Segelmark, Mårten; Tesar, Vladimir; Szpirt, Wladimir M
title: COVID-19 and ANCA-associated vasculitis – recommendations for vaccine preparedness and the use of rituximab
date: 2021-05-03
journal: Nephrol Dial Transplant
DOI: 10.1093/ndt/gfab174
sha: 095589c2e4ff45c4a2c99d199c6c4f65eaae936c
doc_id: 734225
cord_uid: 5eyz2ypq

nan

One year into the COVID-19 epidemic, data regarding a more detailed risk profile and treatment aspects of patients with immune-mediated kidney diseases and ANCA-associated vasculitis (AAV) have remained scarce. The International Registry of COVID infection in glomerulonephritis (IRoc-GN), reported 40 patients with primary glomerulonephritis including AAV. In comparison with 80 hospitalized controls, mortality and acute kidney rates were significantly higher in patients with glomerulonephritis [1] . A UKIVAS analysis of 65 vasculitis patients found associations between co-morbid respiratory disease and prescription of glucocorticoids with severe outcome, Supplementary table [2] Some treatment data is available from rheumatology registry studies. Immunosuppression and outcome of 694 COVID-19 patients with inflammatory rheumatic and musculoskeletal diseases was reported from France. Older age, co-morbidities including chronic kidney disease (CKD), and use of glucocorticoids ≥10 mg/day or equivalent (prednisone), or rituximab were associated with COVID-19 severity [3] . In a recent publication from the COVID-19 Global Rheumatology Alliance of 3729 SARS-CoV-2 infected patients, older age, male sex, CKD and other comorbidities were associated with COVID-19-related death which occurred in 10.5%. Diseasespecific factors, such as moderate/high disease activity, a diagnosis of vasculitis and drugs such as rituximab were associated with mortality, Supplementary table [4] . In neither of these studies were differences between induction or maintenance treatment reported. In a real-life setting, rituximab has frequently been postponed during the pandemic to mitigate the risk of severe SARS-CoV-2 infections. Twenty-one of 206 studied patients with AAV had their rituximab maintenance treatment postponed. Relapses or flares of disease occurred in 12 of these cases.

The disruption of care was highlighted as this may have contributed to delayed relapse diagnosis [5] . These recent findings underline that rituximab treated patients are at risk of developing severe COVID-19, but effective treatment needs to be maintained to reduce the risk of disease relapse in AAV.

The impact of the pandemic has varied between countries and regions. Risk profiles of patient groups and therapies have emerged and become more apparent with cases of COVID-19 prior to and after AAV diagnosis, and in some cases concurrently. How to best treat new or relapsing AAV needs consideration since the pandemic is not over. Glucocorticoid therapy as induction should preferably be dosed in the range of 0.5 mg/kg/day or equivalent (prednisone) and reduced to less than 10 mg/day as soon as possible. Rituximab may also constitute an additional risk. It is however essential to not delay effective treatment of new AAV and RPGN disease and importantly treat relapses adequately. Cyclophosphamide or MMF induction, or even methotrexate depending on kidney function may be alternatives [6] .

Whether patients with rituximab maintenance therapy without or on a low dose of corticosteroids have lower COVID-19 associated risks needs to be studied further.

Concurrently, rituximab has been discussed as a potential therapy in severe COVID-19. Some patients produce antibodies that functionally block the production of interferon-stimulated gene-expressing cells, which are associated with milder disease forms [7] .

COVID-19 vaccines are the most promising approach to rein in the current pandemic. It is nevertheless possible that COVID-19 vaccine efficacy and response rates are lower in patients with immunosuppressive therapy and CKD than in the pivotal studies published so far [8] .

There may be a concern of vaccines provoking disease relapses but immunization against influenza does not appear to increase the relapse rate in patients with AAV [9] . The use of anti-CD20 monoclonal antibodies such as rituximab is of particular concern as it induces rapid and prolonged B-cell depletion abrogating humoral immunity and thereby vaccine response. In rheumatoid arthritis (RA) patients, influenza vaccination 1-2 months after rituximab did not exhibit an IgM or IgG response compared with a measurable IgG response in rituximab treated RA subjects 6-10 months before vaccination [10] . Similar concerns have been raised by the hematology and neurology communities leading to suggestions for an optimal time-window to vaccinate individuals treated with B-cell depleting therapies that will allow immunity to new infections [11] .

"Vaccine readiness" needs to take two scenarios into account: induction of remission in patients presenting with a new diagnosis or relapse and maintenance of remission. In patients with a new diagnosis or relapse of AAV, an alternative therapeutic approach to rituximab may be chosen to achieve remission. During the maintenance phase, we suggest that the time-window before SARS-CoV-2 vaccine administration should be a minimum of 6 months after rituximab.

AAV patients have been shown to have considerably longer time to B-cell repopulation after rituximab as compared with RA and other connective tissues diseases [12] . In addition, previous investigations indicated that the production of neutralizing antibodies and specific vaccination responses are blunted until B cells repopulate ( Figure. 1), which may argue for measurements of B cells before vaccines are scheduled as it may vary between individuals. Again, the time frame after the last vaccine dose should be 4 weeks before B-cell depletion therapy is again given. We also suggest that antibody response and potentially cellular immunity is monitored regularly with an appropriate assay and that booster doses are considered if serology responses decline or SARS-CoV-2 variants of concern with reduced effectiveness for current vaccines emerge.

Vaccine "rollout" to this vulnerable patient groups has been slow in several countries including the European Union. Most will tailor maintenance treatment and likely delay additional doses of rituximab. Again, temporary application of less effective maintenance agents (e.g. azathioprine) might be considered, with a potential switch to rituximab once an appropriate immune response is ensured. Finally, little is known about SARS-CoV-2 immunity in AAV patients after having experienced COVID-19, and even less if this will be affected by rituximab.

Repeated serology monitoring and a readiness to administer booster doses may be a reasonable approach. Effects on T cell immunity are unclear, but remain likely unchanged following anti-CD20 depleting therapy. The most promising vaccine platforms include mRNA vaccines, replicationdefective viral vector vaccines, purified protein vaccines, and inactivated virus vaccines. The efficacy estimates are either published phase 3 trial results or based on press releases. Notably, most COVID-19 vaccine candidates have been tested in a "healthy" population, and patients with autoimmune diseases and receiving immunosuppressive measures have been excluded from major trials.

The authors received no funding in relation to this paper.

A.B. reports personal fees from AstraZeneca, ChemoCentryx, Merck/MSD, Vifor, and Abbvie. 

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

Risk factors for severe outcomes in patients with systemic vasculitis & COVID-19: a bi-national registry-based cohort study

Epub ahead of print

Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: data from the French RMD COVID-19 cohort of 694 patients

COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry

The impact of COVID-19 pandemic on patients with ANCA associated vasculitis

Immunotherapy for ANCAassociated vasculitis during the COVID-19 pandemic

Global absence and targeting of protective immune states in severe COVID-19

COVID-19 vaccines and kidney disease

Influenza vaccination does not result in an increase in relapses in patients with ANCA-associated vasculitis

subclass) responses after influenza vaccination in rheumatoid arthritis patients

COVID-19 vaccine-readiness for anti

CD20-depleting therapy in autoimmune diseases

B cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: A longitudinal observational study on 120 patients