Neuroimmunomodulation & COVID-19

Coronaviruses are well known respiratory viruses with the capability to invade other systems, and there are a growing number of reports of neurologic damage caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at multiple levels of the nervous system. Neurologic complications appear to be more common in severe coronavirus disease 2019 (COVID-19) with preexisting risk factors, and also related to the degree of hypoxic-ischemic damage or direct damage to the nervous system.¹ At present, the process in the development of these neurologic disorders is not fully understood.

The COVID-19 pandemic has been characterized by a sense of uncertainty and copious production of medical literature, leaving the scientific community with many questions to be answered about the long-term effects of the SARS-CoV-2 infection. This flood of information poses the challenge of navigating a vast array of publications to discern the best evidence-based information and recommendations. This article, based mainly on current available peer-reviewed literature, examines how the use of different immunomodulators and immunosuppressive therapies can affect the risk of acquiring COVID-19 and developing a severe form of the disease. Current recommendations regarding use of these therapies in patients with prior neurologic conditions are reviewed and clarified as well.

Inflammatory Response to SARS-CoV-2 Infection

In the initial asymptomatic phase, which lasts approximately 12 days, there is minimal immune response to SARS-CoV-2 infection. As symptoms develop and the infection spreads,² a strong innate immune response is triggered via toll-like receptors 3, 7, and 8, leading to type I interferon (IFN) production and natural killer (NK) cell activation.³ Adaptive immunity then recruits cytotoxic T cells to kill virally infected cells and stimulates B cells and plasma cells to produce neutralizing antibodies.

SARS-CoV-2, however, has multiple mechanisms that affect the efficacy of the innate and adaptive immune responses. By enhancing proinflammatory immune activation with cytokine overproduction, SARS-CoV-2 resists IFN and directly infiltrates and inactivates monocytes, macrophages, neutrophils, and lymphocytes. Subsequent leukopenia and lymphopenia results while proinflammatory subsets of T cells are increased. This inappropriate overactivation of the immune response is known as a cytokine storm, seen in severe cases of COVID-19 (See Neurologic Manifestations and Associations of COVID-19in this issue). Current studies suggest severe illness results in higher antibody levels, more pronounced lymphopenia, and higher levels of circulating cytokines. Antiviral drug therapies have been developed or repurposed to prevent virus entry, inhibit viral replication, decrease inflammation, or directly inhibit proinflammatory cytokines.³

People who are immunocompromised have a higher risk for severe COVID-19,² and management of neurologic conditions typically treated with immunotherapy is not well established in the context of COVID-19. Available data suggests immunosuppressive therapy should be continued in people who do not have COVID-19.⁴ There is consensus that such individuals should maintain strict precautions to avoid exposure. Viral shedding duration can be extended in the context of immunosuppressive therapy, with subsequent potential to alter the length of illness and duration of quarantine. Vaccination efficacy can be decreased in people who have need of immunotherapies, which is of concern as vaccination becomes available.⁴ Some immunotherapies may increase susceptibility to SARS-CoV-2 infection, which implies consideration of stopping such treatments where the prevalence of COVID-19 is high. Some immunosuppressive therapies, however, are used in severe COVID-19 to try to reduce hyperinflammatory complications. The decision to halt, continue, or initiate immunosuppression in the COVID-19 era of should be catered specifically to each individual, weighing the risk of neurologic disease progression and morbidity against the potential risk of infection.⁴

Neurologic Consequences of COVID-19

Neurologic consequences occur in approximately 26% of COVID-19 cases (See also Neurologic Manifestations and Associations of COVID-19 in this issue)⁵ and may precede other symptoms.¹ SARS-CoV-2 is neurotropic, reaching the nervous system through hematologic spread, direct invasion, or retrograde axonal transport.¹ Individuals with neurologic conditions who have interruptions in care (eg, missed appointments) may have worse outcomes because of overtaxed hospitals and more severe disability because of weakness in bulbar and respiratory muscles.⁶

Immunotherapy for Neurologic Disease in the COVID-19 Era

The challenges related to the use of immunotherapy for neurologic disease are myriad in the context of COVID-19. There is uncertainty regarding susceptibility and persistence of SARS-CoV-2 infection for those receiving immunotherapy, especially medications that reduce lymphocyte count or function. It is unclear how SARS-CoV-2 infection might affect an underlying neurologic disorder usually treated with immunotherapy. The initial antiviral response to SARS-CoV-2 infection is mainly mediated by T and NK cells, but B-cell released antibodies and cytokines play an important role in recruiting T cells for that antiviral response. Immunotherapies can be broad spectrum or target specific cell subsets or cytokines of the immune system. Early, but limited, evidence suggests potential benefits of some immunotherapies on cytokine-release syndrome (CRS), which is often the cause of death in severe COVID-19. At the same time, data also suggest other immunotherapies may increase the risks of contracting the infection and developing severe forms of COVID-19.

In this context, weighing the importance of balancing individual risks and benefits before initiating, continuing, or discontinuing any immunotherapy for neuroimmunologic disorders (NID) is essential in the COVID-19 era.

Nonspecific Immunomodulators

Nonspecific immunomodulators (eg, corticosteroids, plasma exchange [PLEX], and intravenous immunoglobulin [IVIG]) are usually first-line therapy for the management of NID and may have effects on the development of severe COVID-19 and survival (Tables 1 and 2). These therapies may be needed during a severe flare of underlying NID, and it may be acceptable to continue them during the COVID-19 pandemic in those who are at low risk of infection; conversely, it might be wise to discontinue these agents if there is significant immunosuppression, risk of exposure to COVID-19, or hospitalization for severe infection.

Corticosteroids are potent dose-dependent, anti-inflammatory immunosuppressive agents that affect innate and adaptive immunity by impairing neutrophil and monocyte mobilization, inhibiting phagocytic function and production of cytokines, modulating antigen presentation, and suppressing lymphocyte activation. The use of corticosteroids in COVID-19 has been proposed as a means of downregulating proinflammatory cytokine transcription to consequently prevent an extended cytokine response. It is thought this could accelerate the resolution of pulmonary and systemic inflammation in COVID-19-related pneumonia and is currently recommended in the treatment of moderate-to-severe COVID-19.⁴

PLEX removes pathologic antibodies from the blood and is often used to treat NID. In contrast to convalescent plasma, which is obtained from previously infected donors with high specific antibody titers,⁷ IVIG infuses a mixed pool of IgG to enhance immune response. The activity of innate immune cells, complement proteins, and inflammatory cytokines is decreased, and the function of B cells, plasma cells, and T cells is modulated.

Several of the nonspecific immunomodulators interfere with metabolism related to transcription and DNA or RNA synthesis, including azathioprine, which inhibits DNA and RNA production by inhibiting purine synthesis in T cells.⁸ Similarly, mycophenolate mofetil inhibits guanosine nucleotide synthesis, resulting in T- and B-cell cytotoxicity and lower resulting antibody responses.⁸ Methotrexate has immunomodulatory activity through preventing adenosine and guanine metabolism, and cyclosporine blocks cytokine gene transcription in activated T cells and blocks further T-cell activation. Cyclophosphamide is an alkylating agent that suppresses the bone marrow.⁸ Leflunomide inhibits pyrimidine, tyrosine stimulation, and nuclear factor kappa beta.³

Chloroquine and its derivative hydroxychloroquine reduce cytokine production and toll-like receptor signaling,⁷ resulting in antimalarial, antiviral, and immunoregulatory properties, whereas teriflunomide decreases cytokine release from monocytes, which may have a beneficial effect in COVID-19 infection. Thalidomide inhibits tumor necrosis factor (TNF) and stimulates T cells by an unclear mechanism of action. Studies suggest a beneficial effect in reducing lung injury caused by viral infections, reduction in concentrations of inflammatory cytokines (interleukin [IL]-6 and TNF), and nuclear factor kappa beta activity.³

The Janus kinase (JAK) inhibitors, tofacitinib, ruxolitinib, and baricitinib, are potent selective inhibitors of the kinase activity of JAK1 and JAK2 characterized by temporary immunosuppression owing to their short half‐life.⁸

Specific Immunomodulators

Immunomodulators such as alemtuzumab, cladribine, fingolimod, and dimethyl fumarate can cause lymphopenia and may create a higher risk for COVID-19 infection, whereas glatiramer acetate, IFN-Β, eculizumab, tocilizumab, and infliximab cause minimal-to-no immunosuppression and may have a protective effect on CRS (Tables 3 and 4). AntiCD20 and antiCD19 therapies affect mainly B cells and cause moderate immunosuppression. Along with therapeutic immunosuppression, several other factors (eg, infusion at home or in hospital, possible rebound disease with treatment interruption, and severity of underlying NID) should be considered when choosing treatment.

Rituximab, ocrelizumab, obinutuzumab, veltuzumab, and ofatumumab are monoclonal antibodies (MAbs) to CD20 that deplete B cells. More than 30 cases of COVID-19 in people receiving rituximab have been reported. Of these, 3 had a serious infection and 2 died.^9-12 Of 130 cases of people treated with ocrelizumab who had COVID-19, 30 were severe.^9-11,13

Ofatumumab is an autoinjectable subcutaneous dose of antiCD20 MAb approved in September 2020 for relapsing and secondary progressive multiple sclerosis (MS). Inebilizumab is an antiCD19 MAb for neuromyelitis optic spectrum disorders (NMOSDs) that can be used cautiously for NMOSD that has not responded to other treatment options. Alemtuzumab is a MAb to CD52 that depletes T and B cells and is reserved for people with severe MS. Data regarding COVID-19 in people treated with ofatumumab, inebilizumab, and alemtuzumab^14,15 are limited or lacking. Ofatumumab may represent a useful outpatient therapy during this pandemic as an at-home self-administered therapy.

Cladribine is a synthetic purine nucleoside analogue that inhibits DNA synthesis in circulating T cells and B cells to deplete lymphocytes, although less profoundly than that seen with alemtuzumab. Dimethyl fumarate (DMF) also creates an anti-inflammatory state by reducing lymphocyte counts and activates nuclear-related factor 2 (NRF2)-mediated antioxidative response pathways leading to additional cytoprotective effects in nervous system and lung cells.^10,16

Sphingosine-1-phosphate receptor (S1PR) inhibitors, fingolimod, siponimod, and ozanimod, entrap lymphocytes in the lymphoid tissue, decreasing circulating lymphocyte counts without reducing total functional lymphocytes. These agents have short half-lives and reversible effects, although the circulating lymphocyte count can be decreased for weeks to months.

IFN-Β blocks the action of IFN-γ and helps to reduce inflammation. IFN-Β1a levels in lung cells decrease with increasing age, suggesting replacement might confer protection from the risk of COVID-19 infection.^10-12

Glatiramer acetate (GA) is thought to shift the population of T cells from proinflammatory Th1 T cells to regulatory Th2 T cells that suppress the inflammatory response. GA is used to treat relapsing MS and has been shown to block IFN-γ-mediated macrophage activation, which is thought to be essential for the development of COVID-19–related acute respiratory distress syndrome (ARDS).^10,12

Infliximab is a TNF inhibitor often used for neurosarcoidosis. No reports of COVID-19 in people taking infliximab COVID-19 have been reported among those with neurosarcoidosis. Infliximab, however, is often used in inflammatory bowel disease and rheumatologic conditions and very few cases with severe COVID-19 have been reported amongst people with those conditions taking infliximab.¹⁷

Natalizumab is a humanized MAb against α4-integrin that inhibits migration of lymphocytes into the central nervous system.^10,13 Eculizumab is a MAb of C5a and is currently used for myasthenia gravis and NMOSD patients. No COVID-19 case has been reported in a person taking eculizumab.¹⁸ Tocilizumab and satralizumab are humanized antiIL‐6 receptor MAbs used to treat NMOSD. No cases of COVID-19 have been reported in people taking these agents, and tocilizumab is recommended in cases of serious COVID-19 because IL‐6 is among the most important cytokines involved in COVID-19–induced CRS.¹⁹

Initiating Immunotherapy in the COVID-19 Era

In MS, GA and IFN are recommended for mild-to-moderate disease, and natalizumab, cladribine, and rituximab for severe disease if it has not responded to GA or IFN. For MS exacerbation, oral steroids are preferred over IV steroids to reduce the potential for COVID-19 exposure.

In NMOSD exacerbations, IVIG or PLEX are first-line choices and if these have been ineffective, eculizumab or satralizumab can be considered.

In myasthenia gravis (MG), for moderate-to-severe disease requiring a change in therapy, consider eculizumab or maintenance IVIG. During an MG crisis, consider IVIG or PLEX. Consider rituximab only in those failed by other treatments or in severe muscle-specific kinase antibody–positive MG. Avoid starting azathioprine, mycophenolate, or methotrexate because of frequent lab monitoring requirements and slow onset of action.

Maintenance Immunotherapy in the COVID-19 Era

In MS, consider continuing GA, IFN, fingolimod, and DMF. Data regarding the maintenance of other immunotherapies for MS are too limited to make a recommendation.

For NMOSD, continue azathioprine, mycophenolate, and methotrexate. Consider switching from cyclophosphamide to eculizumab, tocilizumab, or satralizumab. For those using rituximab, consider delaying infusion or switching therapy, depending on underlying disease status and COVID-19 risk.

For MG, continue azathioprine, mycophenolate, methotrexate, prednisone, cyclosporine, IVIG, or eculizumab. Consider delaying rituximab infusion or switching therapy unless other treatment fails to be effective and there is demonstrated worsening of MG.

Immunotherapy in COVID-19 Disease

In MS, those receiving GA, IFN, and DMF who develop COVID-19 should continue the same immunotherapy. Consider withholding infusions in people treated with ocrelizumab, rituximab, alemtuzumab, and natalizumab. Data are too limited to make recommendations for other MS therapies at this time.

In people with NMOSD who develop COVID-19, continue eculizumab, tocilizumab, or satralizumab. Consider IVIG or PLEX if an exacerbation of NMOSD develops.

There is a higher risk of MG exacerbation during COVID-19 infection, and trying IVIG or PLEX is recommended for those with worsening MG and continuation of maintenance immunosuppression. Azithromycin and hydroxychloroquine can potentially worsen MG and should be avoided.

The complex decision process of initiating, continuing, or stopping immunotherapy in those with underlying NID during the COVID-19 pandemic should be individualized and guided by an expert in the area who can put in context multiple variables including underlying diagnosis, current disease stage, the individual risk of acquiring infection and developing severe disease, and local behavior of the COVID-19 infection.

Conclusion

This pandemic has brought many challenges for the neurologist and highlights the need for carefully managing patients with underlying NID. Factors for consideration include the current immunotherapy the patient is receiving, the individual potential risk of acquiring COVID-19 and developing a severe infection, or the lack of supportive evidence to guide further therapy. It is recommended to individualize decision management and weigh the risks of continuing immunosuppressive therapy during the COVID-19 pandemic.²⁰ In general, in low-risk cases it may be appropriate to continue prior immunotherapies during the COVID-19 pandemic, recommend self-isolation and further necessary precautions, initiate potent immunosuppressors in cases of life-threatening or disabling relapses of NID as needed, and consider stopping therapy in presence of a severe COVID-19 infection.