Impact of disease-modifying antirheumatic drugs on vaccine immunogenicity in patients with inflammatory rheumatic and musculoskeletal diseases

Abstract

Patients with rheumatic diseases are at increased risk of infectious complications; vaccinations are a critical component of their care. Disease-modifying antirheumatic drugs may reduce the immunogenicity of common vaccines. We will review here available data regarding the effect of these medications on influenza, pneumococcal, herpes zoster, SARS-CoV-2, hepatitis B, human papilloma virus and yellow fever vaccines. Rituximab has the most substantial impact on vaccine immunogenicity, which is most profound when vaccinations are given at shorter intervals after rituximab dosing. Methotrexate has less substantial effect but appears to adversely impact most vaccine immunogenicity. Abatacept likely decrease vaccine immunogenicity, although these studies are limited by the lack of adequate control groups. Janus kinase and tumour necrosis factor inhibitors decrease absolute antibody titres for many vaccines, but do not seem to significantly impact the proportions of patients achieving seroprotection. Other biologics (interleukin-6R (IL-6R), IL-12/IL-23 and IL-17 inhibitors) have little observed impact on vaccine immunogenicity. Data regarding the effect of these medications on the SARS-CoV-2 vaccine immunogenicity are just now emerging, and early glimpses appear similar to our experience with other vaccines. In this review, we summarise the most recent data regarding vaccine response and efficacy in this setting, particularly in light of current vaccination recommendations for immunocompromised patients.

Keywords: antirheumatic agents; methotrexate; rituximab; tumour necrosis factor inhibitors; vaccination.

Figure 1:. Mechanism of the mRNA SARS-CoV-2 vaccine and potential impact of DMARD therapy:

1) The mRNA vaccine is given as an intramuscular injection. 2) Lipid nanoparticles (LPN) coating the mRNA allow uptake into antigen presenting cells (APCs). 3) mRNA is recognized by toll-like receptors (TLR)/retinoic acid-inducible gene (RIG)-I, triggering a type I interferon (IFN) response. 4) mRNA is translated by ribosomes into peptides. 5) Peptides are processed by the proteasome and presented on MHC-I or 6) post-translationally modified into secreted proteins, which can then be taken up by APCs and presented by MHC-II. 7) Dendritic cells (DCs) are trafficked to lymph nodes where they 8) prime CD4+ and CD8+ T cells. 9) CD4+ T cells differentiate into T follicular helper (Tfh) cells, which form germinal centers (GC) or 10) Th1 cells. 11) CD8+ T cells become circulating cytotoxic T cells. 12) In the GC, Tfh cells interact with B cells, resulting in 13) memory B cells (MBC) and long-lived plasma cells (LLPCs) secreting anti-spike protein antibodies (Abs). Low dose methotrexate (MTX) impacts expression of cytokines, B cell and CD8+ T cell responses, with apparent preservation of CD4+ response. Mycophenolate mofetil reduces B and T lymphocyte proliferation. Abatacept is a soluble fusion CTLA-4 IgG, which prevents T cell costimulation. Janus kinase (JAK)-inhibitors reduce signaling by numerous cytokines, of particular importance in mRNA vaccines response are IFNγ, interleukin (IL)-4 and IL-2 signaling. Rituximab depletes B cells by targeting CD20, which is expressed by early B cells but not mature plasma cells. Belimumab binds soluble B lymphocyte stimulator (BLyS), reducing B cell survival. SARS-CoV-2 mRNA vaccine mechanisms depictions are modified from figures attributed to Cagigi/Loré and Bettini/Locci, licensed under CC BY 4.0.