Autoimmune and rheumatic musculoskeletal diseases as a consequence of SARS-CoV-2 infection and its treatment

Abstract

The coronavirus disease-2019 (COVID-19) pandemic is likely to pose new challenges to the rheumatology community in the near and distant future. Some of the challenges, like the severity of COVID-19 among patients on immunosuppressive agents, are predictable and are being evaluated with great care and effort across the globe. A few others, such as atypical manifestations of COVID-19 mimicking rheumatic musculoskeletal diseases (RMDs) are being reported. Like in many other viral infections, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can potentially lead to an array of rheumatological and autoimmune manifestations by molecular mimicry (cross-reacting epitope between the virus and the host), bystander killing (virus-specific CD8 + T cells migrating to the target tissues and exerting cytotoxicity), epitope spreading, viral persistence (polyclonal activation due to the constant presence of viral antigens driving immune-mediated injury) and formation of neutrophil extracellular traps. In addition, the myriad of antiviral drugs presently being tried in the treatment of COVID-19 can result in several rheumatic musculoskeletal adverse effects. In this review, we have addressed the possible spectrum and mechanisms of various autoimmune and rheumatic musculoskeletal manifestations that can be precipitated by COVID-19 infection, its therapy, and the preventive strategies to contain the infection.

Keywords: Autoimmunity; Coronavirus disease-2019 (COVID-19); Rheumatic musculoskeletal diseases (RMDs); Rheumatology.

Fig. 1

Mechanism of autoimmunity through molecular mimicry and bystander activation of antigen-presenting cells and proinflammation. a Molecular mimicry: The processing of cross-reactive peptide and presentation via MHC1 and MHC2 to T cells lead to the generation of autoreactive cells. ACE2 angiotensin-converting enzyme 2, ER endoplasmic reticulum, ERAP endoplasmic reticulum aminopeptidase, MHC major histocompatibility. b Bystander activation of antigen-presenting cells and proinflammation: The cytoplasmic pattern recognition receptors after identifying viral RNA phosphorylates downstream IRF-3, IRF-7, and NFκB leading to the secretion of interferons as well as proinflammatory cytokines. CCL2 chemokine (C–C motif) ligand 2, CXCL8 C-X-C motif chemokine ligand 8, IL interleukin, IRF interferon regulatory transcription factor, ISRE interferon-stimulated response element, MDA-5 melanoma differentiation-associated protein-5, MVAS mitochondrial antiviral-signaling protein, MYD88 myeloid differentiation primary response-88, RIG-1 retinoic acid-inducible gene-I, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells), TLR toll-like receptor, TNF tumor necrosis factor

Fig. 2

Bystander killing: virus-specific CD8⁺ T cells migrating to the infected target tissues and exerting perforin and granzyme-mediated cytotoxicity. The CD4⁺ T cells contribute to this bystander killing by the release of proinflammatory cytokines and enhancing phagocytic activities of the macrophages. The free oxygen radicals and cytokines secreted from the activated macrophages result in bystander killing off the surrounding non-infected cells. Ineffective clearance of these killed cells exposes autoantigen to the antigen-presenting cells, resulting in the generation of autoreactive cells in the presence of the costimulatory molecules

Fig. 3

NETosis: Neutrophils recruited to the target tissues following chemokine IL-8 gradient gets activated by IL-1β and free oxygen radicals leading to a sustained generation of NETosis. NETs carrying autoantigen, which gets recognized by dendritic cells, leads to the activation of autoreactive T cells. IL interleukin, NET neutrophil extracellular traps

Fig. 4

Targeted immunosuppressive therapy for COVID-19: Macrophages play a significant role in cytokine release syndrome associated with SARS-CoV-2 infection. The cells get activated directly by viruses as well as bystander activation with autocrine and paracrine actions of the proinflammatory cytokines mainly derived from the macrophages, NK cells, and T cells. The target of immunosuppressive therapy is denoted by the numbered boxes as described below. The red color box denotes the drugs for which clinical trials are ongoing and the grey color box denotes the drugs for which there is no ongoing clinical trial registered at present for the treatment of COVID-19. (1) TLR7 mediated viral signaling at the endosomal level—> chloroquine and hydroxychloroquine. (2) TLR4-TRIF signaling—> plausible therapeutic target, no approved drug. (3) IRAK4 inhibitor—> PF-06650833, CA-4948. (4) (a) Anti IL-1β—> canakinumab, (b) IL-1 receptor antagonist- > anakinra. (5) TNF inhibitors—> infliximab, adalimumab, etanercept. (6) GM-CSF signaling inhibition—> lenzilumab. (7) (a) Anti IL-6—> siltuximab, clazakizumab (b) Anti IL-6 receptor > tocilizumab, sarilumab. (8) Anti IFN γ—> emapalumab. (9) JAK inhibitor—> baricitinib, ruxolitinib, tofacitinib (multi-cytokine targeted therapy). CCL2 chemokine (C–C motif) ligand 2, CXCL8 C-X-C motif chemokine ligand 8, ACE2 angiotensin-converting enzyme 2, GM-CSF granulocyte–macrophage colony-stimulating factor, IFN interferon, IL interleukin, IRAK4 interleukin-1 receptor-associated kinase 4, IRF interferon regulatory transcription factor, ISRE interferon-stimulated response element, JAK Janus kinase, MDA-5 melanoma differentiation-associated protein-5, MVAS mitochondrial antiviral-signaling protein, MYD88 myeloid differentiation primary response-88, RIG-1 retinoic acid-inducible gene-I, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, STAT signal transducer and activator of transcription, TLR toll-like receptor, TNF tumor necrosis factor