COVID-19 revisiting inflammatory pathways of arthritis
Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome coronavirus 2, which predominantly affects the lungs and, under certain circumstances, leads to an excessive or uncontrolled immune activation and cytokine response in alveolar structures. The pattern of pro-inflammatory cytokines induced in COVID-19 has similarities to those targeted in the treatment of rheumatoid arthritis. Several clinical studies are underway that test the effects of inhibiting IL-6, IL-1β or TNF or targeting cytokine signalling via Janus kinase inhibition in the treatment of COVID-19. Despite these similarities, COVID-19 and other zoonotic coronavirus-mediated diseases do not induce clinical arthritis, suggesting that a local inflammatory niche develops in alveolar structures and drives the disease process. COVID-19 constitutes a challenge for patients with inflammatory arthritis for several reasons, in particular, the safety of immune interventions during the pandemic. Preliminary data, however, do not suggest that patients with inflammatory arthritis are at increased risk of COVID-19.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third zoonotic coronavirus to cross the species barrier, infect humans and become transmitted between humans 1 . Whereas the two other zoonotic coronaviruses, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), could be contained at the regional level, SARS-CoV-2 has led to a global pandemic known as coronavirus disease 2019 (COVID-19). Although COVID-19 usually presents as a mild respiratory disease, like infections caused by the four endemic human coronavirus (HCoV-229E, HCoV-NL63, HCoV-OC43 and HCoV-HKU1), it can occasionally lead to severe alveolar inflammation. In a large study from China, ~15% of SARS-CoV-2-infected patients developed shortness of breath, radiological infiltrates in the lung and a drop in blood oxygen saturation (80% of patients at the time of hospital admission and affects predominantly CD4+ T cells, including effector memory T cells and regulatory T cells 22 . The pathogenesis of COVID-19-associated lymphocytopenia is unknown, but it is thought that lymphocytes redistribute to the lungs. Lessons from previous outbreaks of SARS-CoV and MERS-CoV infections in fact suggest that these viruses induce robust IL-17 production by lymphocytes and that IL-17 boosts the pro-inflammatory nature of the host anti-viral immune response to SARS viruses 27 , 28 . In accordance with this mechanism, concentrations of not only IL-17 but also GM-CSF (another important pro-inflammatory mediator expressed by T helper 17 (TH17) cells) are high in patients with COVID-19 (refs 22 , 23 ). As IL-17 is involved in the recruitment of neutrophils to inflammatory sites, it is likely that this cytokine — which, alongside TNF, is an important therapeutic target in spondyloarthritis and psoriatic arthritis — might contribute to the development of COVID-19. Notably, IL-17 is not the only T cell-derived effector cytokine that is elevated in COVID-19 and might contribute to lung inflammation. Concentrations of IL-4, IL-9 and IL-13, which are associated with type 2 immunity, bronchial hypersensitivity and increased mucus production, are also high in patients with COVID-19 (ref. 22 ). These mediators reflect activation of TH2 cells, TH9 cells, eosinophils and type 2 innate lymphoid cells in the lungs of patients with COVID-19. Although these mediators might have a pro-inflammatory function in the lungs in COVID-19, several previous studies have shown that they act differently in the joints and contribute to resolution of arthritis 29 , 30 .
Arthritis drugs for COVID-19?
SARS-CoV-2, like SARS-CoV and MERS-CoV, has the capability to trigger a massive immune response associated with a cytokine storm, leading to ARDS, which can be lethal in the most serious cases of COVID-19 (refs 23 , 31 , 32 ). Hence, anti-cytokine intervention, which does not increase the risk of viral infection and thus might not affect viral clearance but would inhibit the hyper-inflammatory state in COVID-19, might be beneficial 33 . By contrast, broad immunosuppression, especially by targeting lymphocyte function, for example, with glucocorticoid therapy, could be harmful in COVID-19, which itself is associated with substantial lymphocytopenia. Indeed, none of the current data on SARS-CoV-2, SARS-CoV and MERS-CoV supports the use of glucocorticoids 12 , 13 , 14 . Thus, the use of anti-cytokine agents in the most critical phases of COVID-19 is supported by a rationale that overcomes potential concerns about dampening the host response to the virus. Which pro-inflammatory cytokine is most critical to the pathogenesis of COVID-19 is currently unknown, although IL-6 seems to be pivotal 34 , 35 . Indeed, the results of a Chinese study 36 exploring the use of the IL-6 receptor (IL-6R) antagonist tocilizumab are encouraging, and several trials with IL-6R antagonists (tocilizumab and sarilumab) and IL-6 inhibitors (sirukumab) have now been initiated 37 , 38 . IL-1 inhibition also seems to make sense in the treatment of COVID-19, as IL-1β is produced by AT2 cells upon infection with SARS-CoV 24 and is an important effector cytokine of innate immunity, controlling neutrophil and macrophage function. Indeed, IL-1β inhibition with high-dose anakinra or with canakinumab is currently being evaluated as treatment for COVID-19 (refs 39 , 40 ). TNF has been proposed as a target for the treatment of SARS-CoV 41 and more recently for SARS-CoV-2 infection 42 . Preclinical data suggest that TNF inhibition mitigates viral pneumonia 43 , and clinical data indicate that patients being treated with TNF inhibitors for inflammatory diseases do not have a worse outcome of COVID-19 than those treated with conventional drugs 44 . Currently, a study evaluating the TNF inhibitor adalimumab in COVID-19 has been registered in the Chinese Clinical Trial Registry (ChiCTR2000030089) 45 .
Beyond the drugs capable of selectively blocking cytokines, much attention has been paid to drugs that modulate the production of more than one cytokine, such as Janus kinase (JAK) inhibitors. As mentioned above, SARS-CoV-2 enters target cells through receptor-mediated endocytosis 13 . Some of the identified regulators of clathrin-mediated endocytosis are members of the numb-associated kinase family, such as AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK). Inhibition of AAK1 might prevent the virus from entering lung cells 46 , and the JAK inhibitor baricitinib is able to effectively inhibit AAK1 and GAK 47 . Moreover, as an inhibitor of JAK1 and JAK2, baricitinib inhibits IL-6 and GM-CSF, concentrations of which are elevated in COVID-19 (ref. 22 ). At least five studies with baricitinib, one with tofacitinib and one with ruxolitinib are ongoing 48 .
GM-CSF is a key mediator for macrophage and neutrophil attraction from the bone marrow to inflamed tissues and is a validated target for the treatment of RA. GM-CSF thereby represents a link between T cell activation and innate immune effector cells, as TH17 cells are a major source of GM-CSF 49 . As GM-CSF levels are high in COVID-19 ((ref. 22 ), studies have been initiated of neutralizing antibodies that block GM-CSF in COVID-19 (ref. 50 ).
Cytokine inhibition and viruses
Although most of the cytokines induced in COVID-19, as well as those being targeted in RA and other forms of inflammatory arthritis, are important in mounting an inflammatory response, they might not be essential for controlling virus clearance. In support of this concept, therapeutic neutralization of TNF, IL-6 and IL-1β yields a moderate increase in bacterial but not viral infection. Notably, although the incidence of influenza and the risk of developing complications from influenza infection is 2.75-fold higher in patients with RA than in individuals without RA, no signal related to cytokine inhibitor treatment has been observed 51 . In addition, patients with RA undergoing treatment with TNF inhibitors achieve a normal immune response to influenza vaccination, further supporting the concept that effector cytokines induced by SARS-CoV-2 and in RA are critical for inflammatory responses but not for viral clearance. As a matter of fact, data from patients with RA and those with inflammatory bowel disease treated with TNF inhibitors seem to be reassuring, with no increase in the risk of COVID-19 (refs 44 , 52 , 53 ). However, further data on the adverse, or potentially even beneficial, effects of cytokine inhibitors in respiratory infections need to be collected, as preclinical data (for example, on IL-6) have also suggested that cytokines not only have an important role in the inflammatory response against viruses but are also required to mount a proper immune response against the virus 54 .
In contrast to compounds directed against single pro-inflammatory cytokines, the use of JAK inhibitors might raise some concern, in principle, with respect to viral clearance. Type I interferons are among the most powerful molecules for preventing viral replication. These molecules exert their action via JAK–STAT signalling, which activates interferon-stimulated genes to enable elimination of virus-infected cells. Many viruses have developed strategies to counteract the effects of type I interferons, some of which antagonize the JAK–STAT pathway 55 . Consequently, JAK blockade most likely impairs interferon-mediated anti-viral responses, which could promote rather than inhibit SARS-CoV-2 infection. This mechanism explains the increased risk of varicella zoster and herpes simplex virus infection reported in patients treated with JAK inhibitors 56 . Notably, viral infections (including herpes zoster and herpes simplex) can account for up to 10% of community-acquired and up to 50% of ventilator-associated pneumonia cases 57 . Moreover, lymphocytopenia seems to be a negative prognostic factor in severely affected patients with COVID-19 (ref. 58 ), and JAK-inhibitor-induced leukopenia is a well-known adverse event. Therefore, while awaiting results from ongoing studies, a word of caution is warranted before suggesting JAK inhibition in this setting 59 , 60 .
Beyond studies aimed at identifying an effective treatment for COVID-19, the availability of a specific vaccine for SARS-CoV-2 will certainly offer a possible definitive exit from the pandemic. As of 8 April 2020, the global COVID-19 vaccine research and development landscape included 115 vaccine candidates, of which 78 are being actively pursued at the moment 61 . In general, it should be emphasized that, despite many discussions about the safety and efficacy of vaccination in patients receiving immunosuppressive therapy, data from large cohorts indicate that vaccines might be safer and more effective in this setting than previously thought 62 .
COVID-19 effects on rheumatology
The COVID-19 pandemic is having a profound effect on rheumatology practice. On the one hand, a large part of the usual activity of rheumatology units has been absorbed by the growing need to manage patients with COVID-19; on the other hand, the need to maintain the high standard of care required for the treatment of rheumatic diseases remains 63 . The reduction in the number of physicians available in rheumatology, owing to absence because of disease, quarantine or involvement in the COVID units, is difficult to reconcile with the treat-to-target approach that has now become the core of the treatment of all chronic inflammatory diseases. In addition, ensuring the proper evaluation of patients receiving immunomodulatory drugs and the timely management of disease flares becomes increasingly challenging in this context. Rheumatologists should reorganize their work by trying to postpone all non-urgent visits and weighing the potential harm of delaying an in-person visit against the potential harm of COVID-19 infection. We are learning how to make a virtue of necessity by unlocking a new era in patient management. Indeed, the COVID-19 pandemic has suddenly disrupted the traditional model of health care, both for patients with rheumatic diseases and for rheumatologists, accelerating the transition to remote health care 64 .
Finally, the widespread use of anti-rheumatic drugs in patients with COVID-19 in areas affected by the pandemic, in a fast and sometimes irrationally growing market, could endanger supplies of these drugs for patients with rheumatic diseases 65 . This challenge is already being faced in Europe and the USA regarding the use of hydroxychloroquine, chloroquine and tocilizumab 66 . Regulators and manufacturers will have to keep this problem in mind to avoid unexpected and regrettable disease recurrence in patients with rheumatic disease owing to suspension of treatment.
The pattern of pro-inflammatory effector cytokines in the alveolar membranes during severe COVID-19 shares similarities with the primary cytokines targeted in the treatment of RA (Table 1 ). Both diseases lead to profound inflammation of structures that form the inner surfaces of the body and induce tissue destruction and responses that lead to organ failure. COVID-19 is characterized by an excessive or uncontrolled host immune response, elicited by alveolar epithelial cell damage and T cell activation in the lungs that triggers exaggerated local production of pro-inflammatory effector cytokines and leads to the attraction of large numbers of neutrophils and macrophages to the lungs. Barrier damage, T cell activation, effector cytokine production and neutrophil influx are also key features of synovitis, and some of the mediators are shared between COVID-19 and RA. The bulk of inflammation and structural damage in COVID-19 is limited to the lungs, which are progressively destroyed. Furthermore, and most likely owing to robust IL-6 activation, COVID-19 leads to systemic acute-phase responses, which are shared with RA. Whether cytokine inhibition can block this process remains to be determined, but a rationale exists for this approach. Surprisingly, the original widespread concerns about using cytokine inhibitors in a potentially life-threating infectious disease such as COVID-19 have been balanced by the recognition that a pathological hyper-inflammatory state is driving the pathology and might require therapeutic cytokine inhibition. These concepts will also affect our advice to patients with arthritis about whether to stop or continue anti-rheumatic therapy. Given that most of these treatments do not increase the risk of viral pneumonia, that glucocorticoids, which are often used to treat flares, are potentially deleterious in COVID-19, and that preliminary data from high-risk areas do not suggest an increased risk of COVID-19 in patients with arthritis, anti-rheumatic therapy should be continued during the pandemic and not be pre-emptively stopped.
Table 1 Comparison of mechanistic disease features in COVID-19 and RA
Wu, F. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020).