– A Position Statement from APLAR
Lai-Shan Tam1, Yoshiya Tanaka2, Rohini Handa3, Chi-Chen Chang4, Yew Kuang Cheng5,6, Nazrul Isalm7, Mengtao Li8, Jose Paulo Lorenzo9, Yeong-Wook Song10, Kazuhiko Yamamoto11, Xiaofeng Zeng8, Syed Atiqul Haq12
1Department of Medicine and Therapeutics, The Chinese University of Hong Kong
2The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
3Apollo Indraprastha Hospitals, New Delhi, India
4Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
5Allergy, Arthritis & Rheumatism Clinic, Farrer Park Hospital
6Yong Loo Lin School of Medicine, National University of Singapore
7Dept. of Rheumatology, BSMMU, Dhaka, Bangladesh
8Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, National Clinical Research Center for Dermatologic and Immunologic Diseases, Ministry of Science & Technology, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, China
9Makati Medical Center, Philippines
10Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
11Laboratory for Autoimmune diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
12BSM Medical University, Dhaka, Bangladesh
Professor Syed Atiqul Haq
BSM Medical University, Dhaka, Bangladesh
The outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in China in December 2019. This disease now affects the whole world. Patients with rheumatic diseases are at higher risk of respiratory infections including influenza and pneumococcal pneumonia, which is attributed to the underlying disease, comorbidities and immunosuppressive therapy (1), but to date we lack good information about the virus SARS-CoV-2. Nonetheless, immunosuppressive treatments are essential to control disease activity and prevent functional deterioration in these patients. Rheumatologists need to be vigilant in preventing rheumatic disease patients from contracting the disease during this pandemic, especially patients with chronic lung problems (e.g. scleroderma with lung fibrosis) and chronic kidney disease (e.g. lupus nephritis) and those on high dose glucocorticoids and immunosuppressants. (Panel 1)
In the desperate search to find effective treatments for COVID-19, drugs largely used by rheumatologists have entered the spotlight, including the caution against use of non-steroidal anti-inflammatory drugs (NSAIDs), the potential of antimalarials and biologic disease-modifying anti-rheumatic drugs (bDMARDs) e.g. anti-interleukin-6 (IL-6) and targeted synthetic DMARDS (tsDMARDs) Janus kinase (JAK) inhibitors to manage cytokine storm syndrome (CSS)/cytokine release syndrome associated with COVID-19. Here, we try to provide guidance regarding clinical decision making both for patients with COVID-19 and those with rheumatic diseases, and strategies to mitigate further harm to these patients.
An Asia Pacific League Against Rheumatism (APLAR) COVID-19 task force comprising rheumatologists from 9 Asia Pacific countries was convened on March 31, 2020. A set of guidance statements was developed and refined based on best available evidence up to April 26, 2020 and expert opinion. Given the overall limited nature of the data, a systematic review was not performed. The final guidance statements integrate both the task force members’ assessment of the evidence quality and the ratio of risk and benefit from the treatment or action. We assert that the key guiding principle should be to “first do no harm,” especially given the unknown efficacy of proposed DMARDs and biologics and their established potential harms. This guidance document has been reviewed and endorsed by the APLAR executive committee and the APLAR scientific committee chairpersons.
How can we minimize the risk of rheumatic disease patients from exposure to COVID-19?
In the absence of a vaccine or a therapeutic agent, a “mitigation approach”, including “social-distancing”, frequent hand washing and quarantining strategies are the primary intervention to hamper the spread of infection (2). Another approach, known as “suppression strategies” includes strict lockdown measures – social distancing in entire populations, the closure of schools and community spaces, aggressive case finding and contact tracing, have succeeded in maintaining low case counts of COVID-19. During this extraordinary time, the rheumatology community faces unprecedented challenges as care could be postponed/delayed or handled through virtual care to minimize contact exposure and practice social distancing.
Comorbid conditions were common in patients with COVID-19 (3). Smoking can cause an increase in the release of IL-6 in bronchial epithelial cells (4), and upregulate angiotensin-converting enzyme-2 (ACE2) receptor, the known receptor for SARS-CoV (5). This is particularly relevant as some of the Asia Pacific countries, e.g. China, has a high male smoking rate (6). Globally the quality of evaluation, monitoring and treatment of comorbidities in rheumatic disease patients is variable with considerable scope for improvement (7). Rheumatologists should be vigilant in assessing and managing comorbidities not only to improve morbidity and mortality, but hopefully may minimize risk of COVID-19 in rheumatic disease patients.
Non-steroidal anti-inflammatory drugs (NSAIDs)
In patients with acute respiratory tract infections, short-term use of NSAIDs are associated with increased risk of cardiovascular events and nephrotoxicity (8-10), higher rates of complications, and delays in the prescription of effective antibiotic treatment (11). Despite the lack of evidence relating specifically to people with COVID-19, regular NSAID use should not be recommended as the first line option for managing the symptoms of COVID-19 (12). Nonetheless, arthritis patients taking NSAID for symptomatic relief should continue their treatment as needed.
Use of Immunosuppressants and Risk of COVID-19 Infection
Epidemiologic studies identified advanced age, male sex and presence of comorbidities (hypertension, obesity, diabetes, coronary heart disease, chronic obstructive lung disease and chronic kidney disease) as poor prognostic factors for COVID-19 (13). Despite the lack of data on the true prevalence and risk of COVID-19 in rheumatic disease patients, immunosuppressed status (the use of chemotherapy or conditions requiring immunosuppressive treatment) was not reported to be a risk factor and risk of adverse outcome. One patient with systemic sclerosis-associated interstitial lung disease (SSC-ILD) on tocilizumab and 7 patients on bDMARDs or tsDMARDs who developed COVID-19 recovered uneventfully (14-16). Nonetheless, at least two patients on rituximab (17) developed respiratory failure and one of them died despite treatment with tocilizumab (18). In order to gather real-world data to inform treatment strategies and better characterise individuals at increased risk of infection, the COVID-19 Global Rheumatology Alliance has successfully developed online portals and case report forms to enable healthcare providers around the world to enter information on individuals with rheumatic disease who have been diagnosed with COVID-19, with clinical data of the first 110 patients published (19). For now, patients with stable rheumatic diseases should continue their treatment. In case of infection (including COVID-19), treatment of infection gains precedence and immunosuppressive treatment may be de-escalated or temporarily withheld in consultation with the treating rheumatologist. (Panel 1)
Acute lung injury and acute respiratory distress syndrome (ARDS) are partly caused by host immune responses. Severe COVID-19 associated pneumonia patients may exhibit features of systemic hyper-inflammation or cytokine storm syndrome (CSS). COVID-19 infection with CSS typically occurs in subjects with ARDS and historically, non-survival in ARDS was linked to sustained interleukin-6 (IL-6) and IL-1 elevation (20). Corticosteroids suppress lung inflammation but also inhibit immune responses and pathogen clearance. The effectiveness of adjunctive glucocorticoid therapy in the management of COVID-19 infected patients remains controversial (21, 22). Until results from ongoing randomized-controlled trials are available, the World Health Organization (WHO) has advised against routine use of systemic corticosteroids for treatment of viral pneumonia outside of clinical trials unless they were indicated for other reasons (e.g. septic shock) (Panel 2). In rheumatic disease patients on long-term steroid, it is very important to remind them not to stop their prednisone even if they develop symptoms suggestive of COVID-19 (Panel 1). For patients with active rheumatic disease, after excluding concurrent active infection, the prednisone dose could be increased carefully according to the severity of the organ manifestation, in spite of the risk of COVID-19.
Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs)
Preclinical and limited clinical data suggested that HCQ and chloroquine (CLQ) have antiviral activity against SARS–CoV-2 (23-25). In contrast, a small but randomised study from China in patients with mild to moderate COVID-19 treated with HCQ or placebo found no difference in recovery rates (26), and French investigators failed to confirm antiviral activity or clinical benefit of the HCQ and azithromycin combination in 11 hospitalised patients with severe COVID-19 (27). In a French series of 17 SLE patients with COVID-19 on long-term HCQ, 11 (65%) and 5 (29%) developed respiratory failure and ARDS respectively despite having blood HCQ concentrations within therapeutic range for the management of SLE (28). Whether this blood HCQ concentrations may be effective for the antiviral activity against SARS–CoV-2 remained uncertain. Nonetheless, data from this study suggests that HCQ may not be able to prevent severe COVID-19 in these patients. Food and drug administration (FDA) cautioned against use of HCQ or CLQ for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems (Panel 2). The APLAR task force agreed that there are insufficient clinical data to recommend either for or against HCQ or CLQ for COVID-19, clinicians should monitor the patient for adverse effects, especially prolonged QTc interval. Health authorities should ensure adequate supply of these drugs since the HCQ shortage not only will limit availability to patients with COVID-19 if efficacy is truly established but also represents a real risk to patients with rheumatic diseases.
On the other hand, rheumatologists should remind patients to continue HCQ and not to taper the dosage even if they develop symptoms suggestive of COVID-19 and reassurance should be given that this drug should not increase their risk of infection.
Once hospitalized, for some patients with COVID-19, death can occur within a few days, many with ARDS, and some with multi-organ dysfunction syndrome (MODS) (14). In those critically ill patients, there are both clinical signs and symptoms, as well as laboratory abnormalities, that suggest a CSS is occurring in response to the viral infection. According to data from the Chinese cohorts, patients with severe disease and requiring intensive care often show leucopenia, lymphopenia, significantly higher levels of C-reactive protein (CRP), IL-6, IL-10, and tumour necrosis factor- α (TNF-α) (29). In this setting, biologic drugs selectively blocking inflammatory cytokines, such as TNF-α inhibitors, anti-IL6, anti-IL1 and JAK inhibitors are currently employed in the treatment of severe cases of COVID-19 in an experimental manner or undergoing clinical trials (Panel 2).
Tocilizumab, has been shown effective in treating CSS, a common complication of CAR-T cell therapy used for treating refractory acute lymphoblastic leukemia (30) and may be effective in Chinese COVID-19 patients with severe and critical disease (31). Anti-IL-6R antibody is currently included in the treatment recommendation for Chinese COVID-19 patients (Panel 2). These concepts have led to interests in JAK inhibitors, e.g Baricitinib, as potential treatments for CSS complicated with severe COVID-19.
ACE2 is a cell-surface protein widely existed on cells in the heart, kidney, blood vessels, especially alveolar epithelial cells. SARS-CoV-2 was believed to invade and enter lung cells through ACE2 mediated endocytosis. One of the known regulators of endocytosis is the AP2-associated protein kinase 1 (AAK1). AAK1 inhibitors can interrupt the passage of the virus into cells and can be helpful in preventing virus infections. Baricitinib, apart from being a JAK inhibitor, is also an AAK1 inhibitor. Baricitinib was thought to be a possible candidate for treatment of COVID-19, considering its relative safety and high affinity (32). On the other hand, JAK–STAT signal blocking by baricitinib produces an impairment of interferon-mediated antiviral response, with a potential facilitating effect on the evolution of SARS-CoV-2 infection, and therefore may not be a suitable treatment (33). While we are waiting for the results from the control trials to resolve this controversy, rheumatologists should be particularly cautious of serious infectious events on the use of this agent, in particular viral infection e.g. herpes zoster.
Rheumatologists worldwide are trying new strategies to optimize care for rheumatic disease patients during this unprecedented COVID-19 pandemic. Concerted efforts from health care providers in different health care systems are required to continue clinical assessments and ensure adequate supply of immunosuppressive therapy. Worsening of rheumatic disease may induce a systemic inflammatory state which may represent an adjunctive risk factor for major susceptibility to viral infection. On the other hand, rheumatologists are cautiously enthusiastic that a variety of immune-modulating drugs and targeted cytokine inhibitors available for rheumatic disease patients may also benefit patients as prophylaxis for COVID-19 or with COVID-19 induced CSS. Because of insufficient data, APLAR could not recommend any specific treatments for patients with COVID-19. Nevertheless, rheumatologists/immunologists are expert in the use of these agents and we should be to the forefront in advising around their application noting risks and benefits are not yet clear and should not be taken for granted in COVID-19. We emphasize the ongoing importance of critical review of emerging literature to inform current and future treatment decisions. International registries have been created to collect data on rheumatic patients with COVID-19. Ultimately, time and these registries will tell what the right decision is regarding maintaining current therapy for patients with rheumatic diseases. The APLAR task force will respond quickly and efficiently to place the evidence base behind and update our recommendations should new findings emerge from clinical trials.