Should Immunosuppressive Therapy Be Modified During a Pandemic?

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory Van Stavern, MD Should Immunosuppressive Therapy Be Modified During a Pandemic? Marc A. Bouffard, MD, Michael Levy, MD, Andrew G. Lee, MD, Gregory P. Van Stavern, MD Drs. Lee and Van Stavern The COVID-19 pandemic (for many of us, the first global pandemic in our lifetimes) has challenged the way we practice medicine, both in terms of seeing and evaluating patients, and also in terms of how we treat. Neuroophthalmologists see and manage many patients on immu- nosuppressive therapy, and there has been an ongoing debate about whether such therapy poses a risk and requires modification during a pandemic. Here, 2 experts debate this issue. Should Immunosuppressive Therapy be Modified During a Pandemic? Pro: Marc Bouffard, MD It is an understandable assumption that patients receiving immunosuppressive treatments are likely to be more susceptible to contracting and experiencing poor outcomes from infectious diseases (1). However, many steroid-sparing immunosuppressants do not seem to confer significant risk of a poor outcome from COVID-19 infection (2–4). These data are encouraging but should be interpreted with some caution because of rapidly evolving COVID-management strategies, potentially underpowered analyses of specific immunosuppressants commonly used in neuro-ophthalmic practice, lack of subgroup analyses focused on select populations pertinent to neuro-ophthalmology (e.g., elderly immunosuppressed patients or those on multiple immunosuppressants), and the inherent limitations to observational, retrospective investigation. However, corticosteroids—perhaps the most commonly prescribed immunosuppressant in neuro-ophthalmic practice—do seem to be associated with increased risk in the setting of the COVID19 pandemic. Strategies to limit corticosteroid exposure in select circumstances may allow neuro-ophthalmologists to Department of Neurology (MB), Beth Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Department of Neurology (ML), Mass General and Harvard Medical School, Boston, Massachusetts; Ophthalmology (AL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; and Ophthalmology and Visual Sciences (GVS), St. Louis School of Medicine, Washington University, St. Louis, Missouri. The authors report no conflicts of interest. Address correspondence to Gregory Van Stavern, MD, St. Louis School of Medicine, Washington University, 660 S. Euclid Ave, St. Louis, MO 63110; E-mail: [e-mail] 266 continue to provide high-quality care while mitigating the risk of iatrogenic harm. The relationship between corticosteroid use and COVID19 infection is complex and incompletely defined. Although the use of dexamethasone seems to improve outcomes in patients with severe COVID-19 infection, its use in patients with mild disease may be associated with increased morbidity and mortality (5). Pre-existing corticosteroid use before COVID-19 infection seems to increase the odds of poor outcomes. Brenner et al (2) reported an odds ratio of 6.9 (95% confidence interval 2.3–20.5) for a poor outcome associated with corticosteroid use before COVID-19 infection in patients with inflammatory bowel disease. Pablos et al (3) reported an odds ratio of 2.20 for a poor COVID-related outcome associated with pre-COVID corticosteroid use in patients with inflammatory arthritis or chronic connective tissue disease. In addition, corticosteroid use may increase the likelihood of contracting COVID-19 (6). A number of factors may contribute to the increased chance of contracting and becoming severely ill from COVID-19 in patients on corticosteroids, including iatrogenic hyperglycemia promoting glycosylation of both SARSCoV-2 and pulmonary angiotensin-converting enzyme receptor 2 (7) as well as bacterial and/or fungal superinfection (8). Although the relationship between corticosteroid use and COVID-19 will likely become better-defined over the coming months, neuro-ophthalmologists should be aware of the potential for increased susceptibility to and severity of COVID-19 infection in patients receiving corticosteroid therapy. It is implausible and inadvisable for neuroophthalmologists to completely avoid corticosteroid use when needed to treat sight-threatening diseases, even in the Bouffard et al: J Neuro-Ophthalmol 2021; 41: 266-271 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point setting of the COVID-19 pandemic. Deviation from clear standards of care solely for COVID-19–related concerns is unlikely to be in the patient’s best interest. Brief corticosteroid exposures used to treat entities such as optic neuritis likely pose little harm, and in some cases, more substantial exposure is unavoidable (e.g., in the treatment of giant cell arteritis). However, consideration of the following questions might facilitate modification of practice to mitigate COVID-associated risks while maintaining high-quality care: Does my Patient With Purely Ocular Myasthenia Require Corticosteroids? Provided there is no evidence of appendicular, bulbar, or respiratory involvement, patients with pure ocular myasthenia may not require corticosteroid therapy. Whereas isolated ptosis is frequently manageable with pyridostigmine monotherapy, resolution of diplopia often requires corticosteroid use at doses which predispose patients to contracting and having a poor outcome from COVID-19 (2,3,6,8,9). A reasonable approach to mitigate diplopia while avoiding corticosteroids would be to begin with a trial of pyridostigmine or monocular occlusion with an occlusive contact lens, a patch, or tape occlusion over a spectacle lens (10,11). If corticosteroids are required, close follow-up to rapidly establish the minimum required dose is reasonable. Should the COVID-19 Pandemic Impact the Risk: Benefit Analysis in Prescribing Corticosteroids for Nonarteritic Anterior Ischemic Optic Neuropathy? The use of corticosteroids in nonarteritic anterior ischemic optic neuropathy (NAION) is controversial. Treatment strategies using corticosteroids for approximately 2 months have been proposed (12). Arguments in favor of and against the use of corticosteroids in NAION have previously been explored at length in the Journal of Neuro-Ophthalmology (13–15). I will not recapitulate this debate, but it is worth considering whether the risks of increased incidence and severity of COVID-19 associated with protracted corticosteroid use are justifiable given the absence of Level 1 evidence confirming corticosteroid efficacy for NAION and the advanced age of the typical NAION patient, already a major risk factor for poor outcomes in COVID-19. At a minimum, patients should be aware that the usual risk-to-benefit analysis of protracted corticosteroid use for NAION is influenced by the COVID-19 pandemic. Should I Begin Tocilizumab in Patients With Ophthalmic Manifestations of GCA? Corticosteroids have traditionally been the mainstay of GCA treatment, and high doses of corticosteroids are routinely required for over 1 year. The advanced age of Bouffard et al: J Neuro-Ophthalmol 2021; 41: 266-271 patients with GCA makes this population particularly vulnerable to poor outcomes in the setting of COVID-19 infection (10,11). Tocilizumab is an IL-6 receptor antagonist which facilitates more rapid withdrawal of corticosteroids in patients with GCA than is possible with traditional corticosteroid monotherapy (16) and may confer vision-preserving benefits (17). In patients without select comorbidities, tocilizumab is generally a safe and well-tolerated treatment (16). The potential role for IL-6 receptor antagonism in mediating the excessive inflammatory cascade in patients with COVID-19 is the subject of ongoing investigation. Although there has not been any compelling benefit demonstrated for IL-6 inhibition using tocilizumab or sarilumab regarding COVID-19–related outcomes, these medications do not clearly seem to result in a higher rate of adverse effects (18,19). In the interest of cumulative corticosteroid mitigation in the elderly and thus particularly COVIDvulnerable GCA population, a lower threshold to initiate tocilizumab patients in without contraindications may be appropriate. Should Patients With Neuro-Ophthalmic Sarcoidosis be Transitioned to TNF-Alpha Inhibitors? The relative rarity of neuro-ophthalmic sarcoid limits the ability to conduct robust therapeutic trials. Within those constraints, a recent multicenter analysis of neurosarcoid treatments has suggested excellent efficacy of infliximab (20). The ability to more rapidly transition patients with neuro-ophthalmic sarcoid away from corticosteroid-based regimens and prevent relapses requiring additional corticosteroid treatment may be advantageous in the setting of the COVID-19 pandemic. Furthermore, TNFa-inhibitors do not seem to be associated with poor outcomes in patients who contract COVID-19 (2,3). Should Immunosuppressive Therapy be Modified in Patients With Demyelinating Disease? Paradoxically, the appropriate modification of immunosuppression during the COVID-19 pandemic may be to increase rather than decrease immunosuppression—at least in patients with suboptimally controlled demyelinating disease. Patients may be more at risk from protracted or repeated corticosteroid treatments and inperson interactions with the health care system than from their immunosuppressants. In the case of multiple sclerosis, even medications regarded as potent immunosuppressants such as cladribine (21–26), alemtuzumab (27– 31), and ocrelizumab (32) do not seem to be obviously associated with poor outcomes in otherwise young and healthy individuals. Intravenous immunoglobulin (IVIg) may be the most effective treatment for myelin oligodendrocyte glycoprotein 267 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point immunoglobulin G–associated disorder (MOGAD) (33). Patients with MOGAD are at high risk for chronic relapsing inflammatory optic neuropathy (CRION) and consequent protracted courses of oral corticosteroids, often for 1– 3 months. The use of IVIg may help to promptly and effectively manage MOGAD, mitigating the frequency, duration, and cumulative dose of corticosteroids. Furthermore, IVIg may even confer some degree of protection against COVID-19 as the prevalence of convalescent anti- bodies against SARS-CoV2 in the general population increases. In cases where it does not entail deviation from a clear standard of care, the modification of immunosuppressive strategies in the setting of the COVID-19 pandemic to limit protracted corticosteroid exposure may offer many neuroophthalmology patients a high standard of care while mitigating excess risk of contracting or experiencing a poor outcome from COVID-19. Should immunosuppressive therapy be modified during a pandemic? Con: Michael Levy, MD, PhD, Department of Neurology, Massachusetts General Hospital and Harvard Medical School The argument that immunotherapy should not be modified during a pandemic can be broadly summed up mathematically by the equation: Chance of bad outcome from infection # Chance of bad outcome from modifying immunosuppressive therapy This equation can be broken down into: Chance of bad outcome from infection ¼ infection risk · mortality Chance of bad outcome from modifying immunosuppressive therapy ¼ Degree of change in immune function · risk of relapse · severity of relapse Let us consider each side of this equation. The chance of a bad outcome from an infection is the product of the risk of catching the infection by the risk of a severe outcome. Catching the infection depends on the basic reproduction number (R0) and the behavior of your patients. The R0 of SARS-CoV2 is up to 5.7 (34), which is similar to small pox, twice as infectious as the influenza virus and about half as infectious as the varicella–zoster virus. Without any background immunity in the general population, COVID-19 infected almost 10% of the US population in 1 year despite aggressive measures to curb transmission, such as masking and social distancing (35). Given the highly infectious nature of SARS-CoV2, it is fortunate that the mortality rate remains below 1%. In the general population, the chance of a bad outcome from COVID infection is approximately 2 per 1,000 individuals (36). The greatest risk factor for a bad outcome from COVID seems to be age such that with each decade of age .50 years the chance of a bad outcome increases exponentially (37). Interestingly, immunosuppressive medications do not seem to significantly increase the risk of infection and do not necessarily lead to a bad outcome (38). At the outset of the COVID-19 pandemic, there was concern that a sup268 pressed immune system would be insufficient to fight off SARS-CoV2 infection. However, the data thus far suggest that immunosuppressive medications used for autoimmune diseases do not increase the risk of infection, except for chronic glucocorticoids (3). Furthermore, immunosuppression may be helpful to prevent death from end-stage COVID; steroids and other immunosuppressive medications are now commonly used for hospitalized patients (5). On the right side of the equation, there are many more variables to take into account for each individual patient. Let us consider the 2 ends of the autoimmunity neurology spectrum. For a condition such as multiple sclerosis, a temporary change in immune suppression may not have a significantly negative impact. In fact, most immunosuppressive medications used for multiple sclerosis require monitoring to avoid excessive immunosuppression (39). Reducing immunosuppression in multiple sclerosis could lead to a relapse, but the chance of a severe relapse with permanent neurological damage is low (40). Thus, for multiple sclerosis patients on aggressive therapy who might be suitable for less immunosuppression anyway, the chance of a bad outcome from this change would be low. An example on the other end of the autoimmune spectrum would be a person with neuromyelitis optica spectrum disorder, a condition in which relapses are usually severe, and recovery back to baseline is the exception, not the rule, despite intensive treatment (41). NMOSD at all ages demands consistent preventive therapy of relapses, and lightning of immunotherapy is likely to trigger a relapse with permanent neurological injury (42). (Furthermore, when this patient is hospitalized for a relapse, he/she is likely to acquire COVID and suffer those consequences as well!) One can predict a pandemic in which immunosuppression meaningfully increases the risk of infection. For example, latent varicella–zoster virus and hepatitis B reemergence are increased in the setting of immunotherapy (43). A pandemic with such viruses could shift the balance of the equation such that the risk of a bad outcome of Bouffard et al: J Neuro-Ophthalmol 2021; 41: 266-271 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point infection is made significantly worse or more likely with immunosuppressive therapy. In regard to the COVID-19 pandemic, age seems to be the greatest risk factor for a bad outcome from infection. Older individuals, especially those over age 80, are at high risk of death (37). Fortunately, the use of immunosuppressive medications is inversely correlated with age—older individuals with autoimmune conditions are less likely to be immunosuppressed to begin with. In multiple sclerosis, for example, immune senescence at age w53 years underlies the trend toward reducing immunosuppressive medication use in this age group (44). The same is true in other nonneurological autoimmune diseases and where the risk of immunosuppressive therapy in older patients includes opportunistic infections and cancer (45). In those diseases in which immunosuppressive therapy is required at any age, such as NMOSD, the risk of a bad outcome from reducing immunosuppressive therapy is much greater than the risk of bad outcome from the infection. Indeed, age is the primary determinant of both bad outcomes from COVID-19 and the likelihood of immunosuppressive treatment for autoimmune disease with an inverse relationship. That is, younger people who need immunosuppressive therapy are less likely to have a bad outcome from COVID-19, and older people at risk of a bad outcome from COVID-19 are less likely to use immunosuppressive therapy to begin with. Thus, for this particular pandemic, reducing immunotherapy does not make sense in most cases. Response to Con: Dr. Bouffard Almost a year ago, Dr. Levy and his coauthor Dr. Vishnevetsky published an editorial in Multiple Sclerosis and Related Disorders articulating the challenge in understanding which patient groups were “high risk” for a poor outcome from a novel and poorly understood pandemic (46). Dr. Levy’s message has proven prescient—although advanced age has clearly been established as a serious risk factor for poor COVID-19–related outcomes, some immunosuppressive medications, which were intuitively believed by many to convey serious risk, have been demonstrated to be at least reasonably safe. In his argument, Dr. Levy uses a clear and concise paradigm to weigh risk vs. benefit of modifying immunotherapy in the setting of the COVID-19 pandemic. The differences in our statements seem to result from the inherent complexity in applying that sound framework to neuroophthalmologic practice because we care for both the most resilient populations (i.e., the young) with many reasonably safe immunotherapies (e.g., many MS medications) and for the most vulnerable populations (i.e., the elderly) with other immunotherapies which seem to be reasonably risky (i.e., corticosteroids). Short courses of corticosteroids likely confer little risk, and in some cases, corticosteroid use clearly should not be modified under any circumstances (e.g., intravenous corticosteroids for ophthalmic manifestations of GCA or optic neuritis associated with NMOSD). However, many relevant questions pertaining to protracted corticosteroid use in the setting of COVID-19 remain unanswered. Does the incidence and severity of COVID-19 infection differ between patients with GCA treated with conventional corticosteroid monotherapy vs tocilizumab and an expedited corticosteroid taper as proposed by Stone et al (16)? Does corticosteroid use in patients older than age 50 with ocular myasthenia reach an adequate dose or duration to impact the incidence or severity of COVID-19? Does protracted corticosteroid use in more resilient populations require modification (e.g., slow corticosteroid tapers for MOGAD-associated CRION)? In the absence of robust data to inform these questions, it seems reasonable to consider how neuroophthalmologists might safely avoid, mitigate, or identify alternatives to corticosteroid use when medically appropriate. Response to Pro: Dr. Levy Having drafted our arguments for/against modifying immunotherapy in parallel, it seems positions are not very different. However, on the issue of corticosteroids, Dr. Bouffard provides a detailed analysis of the risks to COVID infection posed by chronic use, which is a point that I mentioned only briefly. In my world of demyelinating disease, I avoid chronic corticosteroids use because of the consequences to bone health, vasculopathy, endocrine dysfunction, and metabolism. With availability of steroidsparing alternatives for long-term management, I failed to Bouffard et al: J Neuro-Ophthalmol 2021; 41: 266-271 consider that corticosteroids are still widely used in many other neuroinflammatory conditions that Dr. Bouffard addressed. I cede my position to Dr. Bouffard’s argument on this issue, and I can only hope that the pandemic prompts aversion of chronic corticosteroids when suitable alternatives are available. On the topic of steroid-sparing agents, including B-cell therapies, interleukin-6 receptor blockers, TNFalpha blockers, and purine/pyrimidine analogs, it seems that Dr. Bouffard and I agree that there are insufficient 269 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point data that these medications pose a significant risk in the COVID pandemic that would prompt modification. I think it is important to consider each individual case in the decision-making process, and I would like to emphasize the point that certain conditions might be able to tolerate a transient modification in treatment with only minor risks, whereas in other conditions, it would be too risky to modify treatment. Neither of us have addressed the issue of modifying immunotherapy before vaccination. With the rollout of the COVID vaccines, immunosuppressive medications would be expected to blunt the efficacy as they do with other vaccines. On the other hand, these medications may also prevent an immunological overreaction to vaccine that can occur in people with autoimmune diseases. Although some doctors have advocated for reducing immunotherapy to optimize the immune response to the COVID vaccine, there are no data that immunotherapy results in COVID vaccine failure. A second booster shot has been suggested as an alternative to augment the immunological response. Summary: Drs. Lee and Van Stavern The COVID-19 pandemic has caused all of us to rethink how we practice medicine, and Drs. Bouffard and Levy have performed a wonderful job presenting their arguments and reviewing the (ever-evolving) literature on this complicated topic. It is clear that a “one size fits all” approach does not work and that evaluating immunosup- pressive therapy in a pandemic may need to be individualized, by a patient and disease process. This also highlights the importance of staying current with the relevant literature, as we continue to learn more about this disease. Skills learned during this climate may ultimately be of use in any future pandemic. REFERENCES 8. Obata R, Maeda T, Do DR, Kuno T. Increased secondary infection in COVID-19 patients treated with steroids in New York City. Jpn J Infect Dis. 2020. 9. Kupersmith MJ, Ying G. Ocular motor dysfunction and ptosis in ocular myasthenia gravis: effects of treatment. Br J Ophthalmol. 2005;89:1330–1334. 10. Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, Ji R, Wang H, Wang Y, Zhou Y. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020;94:91–95. 11. Pennington AF, Kompaniyets L, Summers AD, Danielson ML, Goodman AB, Chevinsky JR, Preston LE, Schieber LZ, Namulanda G, Courtney J, Strosnider HM, Boehmer TK, Mac Kenzie WR, Baggs J, Gundlapalli AV. Risk of clinical severity by age and race/ethnicity among adults hospitalized for COVID19-United States, march-september 2020. Open Forum Infect Dis. 2021;8:ofaa638. 12. Hayreh SS, Zimmerman MB. Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol. 2008;246:1029–1046. 13. Lee AG, Biousse V. Should steroids be offered to patients with nonarteritic anterior ischemic optic neuropathy? J Neuroophthalmol. 2010;30:193–198. 14. Kupersmith MJ, Miller NR, Levin LA. New treatments in neuroophthalmology: the role for evidence. J Neuroophthalmol. 2017;37:1–2. 15. Hayreh SS. Corticosteroid therapy in nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2017;37:349– 350. 16. Stone JH, Klearman M, Collinson N. Trial of tocilizumab in giant-cell arteritis. N Engl J Med. 2017;377:1494–1495. 17. Unizony S, McCulley TJ, Spiera R, Pei J, Sidiropoulos PN, Best JH, Birchwood C, Pavlov A, Stone JH. Clinical outcomes of patients with giant cell arteritis treated with tocilizumab in realworld clinical practice: decreased incidence of new visual manifestations. Arthritis Res Ther. 2021;23:8. 18. Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, Horick NK, Healy BC, Shah R, Bensaci AM, Woolley AE, Nikiforow S, Lin N, Sagar M, Schrager H, Huckins DS, Axelrod M, Pincus MD, Fleisher J, Sacks CA, Dougan M, North CM, Halvorsen YD, Thurber TK, Dagher Z, Scherer A, Wallwork RS, Kim AY, Schoenfeld S, Sen P, Neilan TG, Perugino CA, 1. Martin Paez Y, Bennett JL, Subramanian PS, Pelak VS. Considerations for the treatment of inflammatory neuroophthalmologic disorders during the COVID-19 pandemic. J Neuroophthalmol. 2020;40:305–314. 2. Brenner EJ, Ungaro RC, Gearry RB, Kaplan GG, Kissous-Hunt M, Lewis JD, Ng SC, Rahier JF, Reinisch W, Ruemmele FM, Steinwurz F, Underwood FE, Zhang X, Colombel JF, Kappelman MD. Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: results from an international registry. Gastroenterology. 2020;159:481–e3. 3. Pablos JL, Galindo M, Carmona L, Lledó A, Retuerto M, Blanco R, Gonzalez-Gay MA, Martinez-Lopez D, Castrejón I, AlvaroGracia JM, Fernández Fernández D, Mera-Varela A, ManriqueArija S, Mena Vázquez N, Fernandez-Nebro A. Clinical outcomes of hospitalised patients with COVID-19 and chronic inflammatory and autoimmune rheumatic diseases: a multicentric matched cohort study. Ann Rheum Dis. 2020;79:1544–1549. 4. Andersen KM, Mehta HB, Palamuttam N, Ford D, Garibaldi BT, Auwaerter PG, Segal J, Alexander GC. Association between chronic use of immunosuppresive drugs and clinical outcomes from coronavirus disease 2019 (COVID-19) hospitalization: a retrospective cohort study in a large US health system. Clin Infect Dis. 2021:ciaa1488. (epub ahead of print). 5. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in hospitalized patients with covid-19—preliminary report. N Engl J Med. 2020;384:693–704. 6. Lukin DJ, Kumar A, Hajifathalian K, Sharaiha RZ, Scherl EJ, Longman RS. Baseline disease activity and steroid therapy stratify risk of COVID-19 in patients with inflammatory bowel disease. Gastroenterology. 2020;159:1541– 1544.e2. 7. Brufsky A. Hyperglycemia, hydroxychloroquine, and the COVID19 pandemic. J Med Virol. 2020;92:770–775. 270 Bouffard et al: J Neuro-Ophthalmol 2021; 41: 266-271 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. Unizony SH, Collier DS, Matza MA, Yinh JM, Bowman KA, Meyerowitz E, Zafar A, Drobni ZD, Bolster MB, Kohler M, D’Silva KM, Dau J, Lockwood MM, Cubbison C, Weber BN, Mansour MK. Efficacy of tocilizumab in patients hospitalized with covid-19. N Engl J Med. 2020;383:2333–2344. Della-Torre E, Campochiaro C, Cavalli G, De Luca G, Napolitano A, La Marca S, Boffini N, Da Prat V, Di Terlizzi G, Lanzillotta M, Rovere Querini P, Ruggeri A, Landoni G, Tresoldi M, Ciceri F, Zangrillo A, De Cobelli F, Dagna L; SARI-RAF Study Group; SARIRAF Study Group members. Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study. Ann Rheum Dis. 2020;79:1277–1285. Gelfand JM, Bradshaw MJ, Stern BJ, Clifford DB, Wang Y, Cho TA, Koth LL, Hauser SL, Dierkhising J, Vu N, Sriram S, Moses H, Bagnato F, Kaufmann JA, Ammah DJ, Yohannes TH, Hamblin MJ, Venna N, Green AJ, Pawate S. Infliximab for the treatment of CNS sarcoidosis: a multi-institutional series. Neurology. 2017;89:2092–2100. Celius EG. Normal antibody response after COVID-19 during treatment with cladribine. Mult Scler Relat Disord. 2020;46:102476. De Angelis M, Petracca M, Lanzillo R, Brescia Morra V, Moccia M. Mild or no COVID-19 symptoms in cladribine-treated multiple sclerosis: two cases and implications for clinical practice. Mult Scler Relat Disord. 2020;45:102452. Dersch R, Wehrum T, Fähndrich S, Engelhardt M, Rauer S, Berger B. COVID-19 pneumonia in a multiple sclerosis patient with severe lymphopenia due to recent cladribine treatment. Mult Scler. 2020;26:1264–1266. Gelibter S, Orrico M, Filippi M, Moiola L. COVID-19 with no antibody response in a multiple sclerosis patient treated with cladribine: implication for vaccination program? Mult Scler Relat Disord. 2021;49:102775. Jack D, Nolting A, Galazka A. Favorable outcomes after COVID19 infection in multiple sclerosis patients treated with cladribine tablets. Mult Scler Relat Disord. 2020;46:102469. Preziosa P, Rocca MA, Nozzolillo A, Moiola L, Filippi M. COVID19 in cladribine-treated relapsing-remitting multiple sclerosis patients: a monocentric experience. J Neurol. 2020:1–3. (epub ahead of print). Carandini T, Pietroboni AM, Sacchi L, De Riz MA, Pozzato M, Arighi A, Fumagalli GG, Martinelli Boneschi F, Galimberti D, Scarpini E. Alemtuzumab in multiple sclerosis during the COVID-19 pandemic: a mild uncomplicated infection despite intense immunosuppression. Mult Scler. 2020;26:1268– 1269. Fernandez-Diaz E, Gracia-Gil J, García-García JG, Palao M, Romero-Sánchez CM, Segura T. COVID-19 and multiple sclerosis: a description of two cases on alemtuzumab. Mult Scler Relat Disord. 2020;45:102402. Fiorella C, Lorna G. COVID-19 in a multiple sclerosis (MS) patient treated with alemtuzumab: insight to the immune response after COVID. Mult Scler Relat Disord. 2020;46:102447. Guevara C, Villa E, Cifuentes M, Naves R, Grazia J. Mild COVID19 infection in a patient with multiple sclerosis and severe depletion of T-lymphocyte subsets due to alemtuzumab. Mult Scler Relat Disord. 2020;44:102314. Matias-Guiu J, Montero-Escribano P, Pytel V, Porta-Etessam J, Matias-Guiu JA. Potential COVID-19 infection in patients with severe multiple sclerosis treated with alemtuzumab. Mult Scler Relat Disord. 2020;44:102297. Bouffard et al: J Neuro-Ophthalmol 2021; 41: 266-271 32. Hughes R, Whitley L, Fitovski K, Schneble HM, Muros E, Sauter A, Craveiro L, Dillon P, Bonati U, Jessop N, Pedotti R, Koendgen H. COVID-19 in ocrelizumab-treated people with multiple sclerosis. Mult Scler Relat Disord. 2020;49:102725. 33. Chen JJ, Flanagan EP, Bhatti MT, Jitprapaikulsan J, Dubey D, Lopez Chiriboga ASS, Fryer JP, Weinshenker BG, McKeon A, Tillema JM, Lennon VA, Lucchinetti CF, Kunchok A, McClelland CM, Lee MS, Bennett JL, Pelak VS, Van Stavern G, Adesina OO, Eggenberger ER, Acierno MD, Wingerchuk DM, Lam BL, Moss H, Beres S, Gilbert AL, Shah V, Armstrong G, Heidary G, Cestari DM, Stiebel-Kalish H, Pittock SJ. Steroid-sparing maintenance immunotherapy for MOG-IgG associated disorder. Neurology. 2020;95:e111–e120. 34. Sanche S, Lin YT, Xu C, Romero-Severson E, Hengartner N, Ke R. High contagiousness and rapid spread of severe acute respiratory syndrome coronavirus 2. Emerg Infect Dis. 2020;26:1470–1477. 35. Centers for Disease Control and Prevention. COVID-19: Cases, Data, and Surveillance, Atlanta, GA: CDC, 2021. 36. Johns Hopkins Coronavirus Resource Center. Mortality Analyses. 2021. Baltimore, MD: Centers for Disease Control and Prevention. COVID-19 Hospitalization and Death by Age. 37. Centers for Disease Control and Prevention. COVID-19 Hospitalization and Death by Age, Atlanta, GA: CDC, 2021. 38. Sharifian-Dorche M, Sahraian MA, Fadda G, Osherov M, Sharifian-Dorche A, Karaminia M, Saveriano AW, La Piana R, Antel JP, Giacomini PS. COVID-19 and disease-modifying therapies in patients with demyelinating diseases of the central nervous system: a systematic review. Mult Scler Relat Disord. 2021;50:102800. 39. Gross RH, Corboy JR. Monitoring, switching, and stopping multiple sclerosis disease-modifying therapies. Continuum (Minneap Minn). 2019;25:715–735. 40. Berkovich RR. Acute multiple sclerosis relapse. Continuum (Minneap Minn). 2016;22:799–814. 41. Kleiter I, Gahlen A, Borisow N, Fischer K, Wernecke KD, Wegner B, Hellwig K, Pache F, Ruprecht K, Havla J, Krumbholz M, Kümpfel T, Aktas O, Hartung HP, Ringelstein M, Geis C, Kleinschnitz C, Berthele A, Hemmer B, Angstwurm K, Stellmann JP, Schuster S, Stangel M, Lauda F, Tumani H, Mayer C, Zeltner L, Ziemann U, Linker R, Schwab M, Marziniak M, Then Bergh F, Hofstadt-van Oy U, Neuhaus O, Winkelmann A, Marouf W, Faiss J, Wildemann B, Paul F, Jarius S, Trebst C. Neuromyelitis optica: evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol. 2016;79:206–216. 42. Krumbholz M, Hofstadt-van Oy U, Angstwurm K, Kleiter I, Jarius S, Paul F, Aktas O, Buchholz G, Kern P, Straube A, Kümpfel T. Very late-onset neuromyelitis optica spectrum disorder beyond the age of 75. J Neurol. 2015;262:1379–1384. 43. Forbes HJ, Bhaskaran K, Thomas SL, Smeeth L, Clayton T, Langan SM. Quantification of risk factors for herpes zoster: population based case-control study. BMJ. 2014;348:g2911. 44. Weideman AM, Tapia-Maltos MA, Johnson K, Greenwood M, Bielekova B. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. 2017;8:577. 45. Borren NZ, Ananthakrishnan AN. Safety of biologic therapy in older patients with immune-mediated diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2019;17:1736–e4. 46. Vishnevetsky A, Levy M. Rethinking high-risk groups in COVID19. Mult Scler Relat Disord. 2020;42:102139. 271 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.