|Year : 2020 | Volume
| Issue : 2 | Page : 122-129
Coronavirus disease-19 and rheumatological disorders: A narrative review
Arghya Chattopadhyay, Debashish Mishra, Vikas Sharma, G SRSN K Naidu, Aman Sharma
Department of Internal Medicine, Clinical Immunology and Rheumatology Unit, Post Graduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||29-May-2020|
Dr. Aman Sharma
Department of Internal Medicine, Clinical Immunology and Rheumatology Unit, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
The global spread of coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2, which originated from Wuhan, China, is likely to have an impact on the rheumatological practices due to a dilemma in both continuing and initiating immunosuppressive medications. We reviewed the risk stratification of patients with rheumatological disorders, the safety of various anti-rheumatological drugs, and the role of multiple drugs used by the rheumatologists in managing COVID-19. The score-based risk stratification is helpful in therapeutic decision-making such as self-isolation, continuation, or initiation of immunosuppressive therapy. Most of the immunosuppressive therapies need not be discontinued unless there is an overwhelming infection. The treatment interruption should not be made in fear, and there should be shared decision-making in consultation with the patient. The proposed role of different anti-rheumatic drugs such as hydroxychloroquine and tocilizumab in COVID-19 based on some initial uncontrolled trials and case reports will become clearer when the results of various ongoing well-planned studies become available.
Keywords: Coronavirus disease-19, hydroxychloroquine, rheumatology, severe acute respiratory syndrome coronavirus, tocilizumab
|How to cite this article:|
Chattopadhyay A, Mishra D, Sharma V, K Naidu G S, Sharma A. Coronavirus disease-19 and rheumatological disorders: A narrative review. Indian J Rheumatol 2020;15:122-9
| Introduction|| |
The coronavirus disease-19 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel enveloped, RNA, beta-coronavirus. This was first reported from Wuhan, the capital of Hubei, China, in December 2019., The infection has now been documented in both hospital and community settings from around the world.,,,, On March 11, 2020, the WHO declared COVID-19 as a pandemic. As per the WHO Situation Report-70, published on March 30, 2020, globally, 693,224 people have been affected, leading to 33,106 deaths. Viral infections are known to precipitate various rheumatological disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic vasculitides., However, there are no reports of precipitation or worsening of any rheumatological disorders due to COVID-19 till the time of writing this review. The global spread is likely to have a bearing on the rheumatological practices as most of the patients are on immunosuppression, and there is a dilemma in both continuing immunosuppression in patients on therapy and initiating immunosuppression in patients recently diagnosed to have a rheumatological disorder. Thus, we planned to carry out the review on risk stratification, the safety of the use of various drugs, and the role of the various drugs used by the rheumatologists in managing COVID-19.
We conducted a literature search on MEDLINE (via PubMed), EMBASE, official websites of the American College of Rheumatology (ACR), British Society for Rheumatology (BSR), European League Against Rheumatism (EULAR), Center for Disease Control and Prevention, and World Health Organization (WHO) using keywords such as “COVID-19,” “hydroxychloroquine,” “tocilizumab,” “anti-inflammatory agent, nonsteroidal,” “steroids,” “rheumatology,” “therapeutics.” A hand-picked google search was done to make the search complete. All relevant articles were reviewed.
People living with various rheumatological diseases, especially those who are on a higher dose of immunosuppressive therapy, are at higher risk for getting multiple infections, and COVID-19 would probably be no exception. The BSR has recently proposed a risk stratification algorithm along with a score-based model for patients with rheumatological disorders. Patients have been grouped into high-, moderate-, and low-risk categories based on the type of immunosuppressive they are on and other risk factors. The patients in the high-risk group are those on prednisolone (or its equivalent) of more than 20 mg/day (or ≥0.5 mg/kg) for more than 4 weeks, cyclophosphamide at any oral or intravenous (IV) dose in the last 6 months, prednisolone dose of more than 5 mg/day (or equivalent) for a month along with at least one of the immunosuppressive drugs, biologicals/monoclonal antibodies, or small molecule immunosuppressant (e.g., Janus kinase [JAK] inhibitors), or any two agents from immunosuppressive medications and monoclonal antibodies and small molecules with any of the comorbidities such as age >70 years, hypertension, diabetes, renal impairment, ischemic heart disease, or preexisting lung disease. Immunosuppressive medications include all conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs), calcineurin inhibitors, and mycophenolate as a single agent or in combination, except for hydroxychloroquine (HCQ) and sulfasalazine. All patients with RA–interstitial lung disease (ILD) or connective tissue disorder associated with ILD and patients with pulmonary hypertension come under the high-risk category. Shielding of patients is recommended for this category. The moderate-risk category includes patients with a well-controlled disease activity and without any comorbidity, taking single broad-spectrum immunosuppressive/monoclonal antibody or small molecule, with or without sulfasalazine and/or HCQ at their standard recommended dose. The patients with well-controlled disease and without any comorbidity and on immunosuppressive drugs at standard dose plus single biological or small molecule were also categorized in moderate risk. Social distancing or self-isolation is recommended for this category based on the physicians' discretion.
The category of low risk has been defined as those who are taking HCQ, sulfasalazine, single-agent 6-mercaptopurine, or only inhaled/per-rectal immunosuppressive agents or single-agent 5-ASA medications. Social distancing is recommended as per the general population and self-isolation usually not required. Subsequently, the BSR has proposed a score-based model that is easy to use for daily practice. It divides the patients into three categories, i.e., a score of ≥3 corresponds to the previously proposed high-risk group, a score of 2 corresponds to previous moderate risk, and a score of ≤1 corresponds to previous low-risk category. The Vasculitis UK has also proposed a risk stratification algorithm in vasculitis patients based on age, type of vasculitis, medication, comorbidities, and additional risk factors, such as smoking. In this context, it must be emphasized that such categorization into risk groups is empirical and will need to be validated in prospective data on patients with rheumatic diseases who happen to be afflicted with COVID-19.
| Drugs Used for Rheumatological Disorders and Coronavirus Disease-19|| |
Viral infections are known to precipitate and flare rheumatological diseases, but a sudden stoppage of immunosuppressive agents can cause disease flares as well. Hence, patients should not stop or reduce the dose of immunosuppressive agents themselves. Similarly, patients on long-term steroids must not discontinue them abruptly., Adding a new immunosuppressive agent possibly increases the risk of COVID-19. Hence, it has been advised that a new anti-rheumatic agent must only be started after a thorough review and only if necessary. To avoid unnecessary exposure, routine and “face-to-face” visits should be avoided. Telephone or other means of communication should be encouraged and can be used to triage patients who need to visit the hospital.,
Currently, there is no vaccine available for COVID-19. However, patients need to be vaccinated for other vaccine-preventable infections as per the EULAR and national guidelines. Influenza, pneumococcal, and whooping cough vaccines should be given on a priority basis.
Rheumatologists must adhere to national guidelines about screening, testing, and management of COVID-19 patients. As with any other infections, immunosuppressive therapy can be stopped temporarily during active infection with COVID-19.,
| Nonsteroidal Anti-Inflammatory Drugs|| |
Limited data from observational studies suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in respiratory illnesses leads to increased complications and prolonged disease course. Their use increases cardiopulmonary as well as septic events in patients with respiratory diseases. These concerns have been raised during the recent COVID-19 pandemic also, notably after the French Health Minister issued a statement against the use of “ibuprofen,” one of the commonly used NSAIDs, in COVID-19 patients. The WHO has clarified that currently, there are no data to recommend against the use of ibuprofen and other NSAIDs, and it is best to avoid their self-medication. The U.S. Food and Drug Administration approved the use of other “over-the-counter” agents such as paracetamol instead of NSAIDs, till sufficient data are gathered to make proper recommendations. Other than possible harmful effects, NSAIDs also mask disease-related symptoms and make early diagnosis difficult. The SARS-CoV-2 utilizes the molecule angiotensin-converting enzyme 2 (ACE2) on the cellular surface to gain entry into target cells, such as those in the lung. Since ibuprofen increases ACE2 expression, there remains a potential mechanistic basis for the increased risk of COVID-19 with ibuprofen. Therefore, until further clinical literature emerges in this regard, it may be prudent to exercise caution while using ibuprofen in this group of patients.
| Steroids|| |
Steroids are known to increase infection risk. However, in a meta-analysis that included 21 randomized controlled trials (RCTs), there was no significant increase in infection rates among patients taking low-dose corticosteroids (≤7.5 mg prednisolone per day) as compared to those not on systemic steroids. All guidelines (BSR, EULAR, and national health service (NHS)-England) have cautioned against the abrupt stoppage of corticosteroids in a patient on long-term steroids.,, The decision to taper steroids in case of active infection with COVID-19 must be individualized by the treating team in consultation with a rheumatologist.
| Conventional Synthetic Disease-Modifying Anti-Rheumatic Drugs|| |
The use of conventional synthetic-DMARDs such as methotrexate, azathioprine, leflunomide, cyclosporine, and tacrolimus categorizes patients into the high-risk category. The risk of infection and morbidity is even higher in patients on cyclophosphamide and mycophenolate. The stoppage of immunosuppressive agents carries a risk of disease flare and hence is not recommended.,, If patients with rheumatological disease develop COVID-19, the immunosuppressive medication should be withheld until they recover from active infection., However, patients can continue HCQ and sulfasalazine even during active infection as well.
HCQ is the mainstay of therapy for patients with SLE and some patients with RA. Sudden withdrawal of HCQ for as brief as 2 weeks has a higher flare rate even in previously clinically stable patients. With the emergence of COVID-19, the focus of care “shifts from the needs of the individual (ethical principle of autonomy) to the needs of the community as a whole (ethical principle of distributive justice),” with an idea to serve the maximum number of population with the highest benefit. Given the sudden surge of demand for HCQ after COVID-19 pandemic due to its known antiviral activity, the ethical principle must balance its utilization based on scarce resources. ACR recently proposed the “Guiding Principles from the ACR for Scarce Resource Allocation During the COVID-19 Pandemic” based on the currently available evidence. In this pandemic era, it would be necessary for the health agencies to ensure an uninterrupted supply of HCQ for the patients with various rheumatological diseases, especially SLE, where these interruptions might result in disease flares some of which may be life- or organ-threatening.
| Biological-Disease-Modifying Anti-Rheumatic Drugs and Small Molecules|| |
The use of these agents puts the patients in high- or very high-risk categories. Stopping the drug or reduction in dose is not recommended unless the patient has an active infection. It is advisable to switch to agents that can be administered orally or subcutaneously in place of agents administered via IV route, and this will prevent hospital visits and reduce infection risk. Patients on stable doses of rituximab need to be assessed if the same can be deferred for the time being. Similarly, zoledronate infusion can also be postponed up to 6 months.
| Immunomodulators in the Treatment of Coronavirus Disease-19|| |
While the medication and the preventive vaccine are currently far-fetched for COVID-19, it is interesting to note that a few of our commonly used anti-rheumatic drugs have been proposed as potential therapeutic agents against this virus in some studies. Increased levels of pro-inflammatory cytokines have been found in COVID-19 patients of which elevated interleukin-6 (IL-6) and hyperferritinemia correlated with disease severity and mortality.
The role of anti-IL-6 and other cytokine-blocking agents in the treatment of COVOD-19 is the current area of research interest.
Recent studies have shown HCQ to have more potent antiviral action than chloroquine.,,, HCQ at an oral loading dose of 400 mg twice daily, followed by 200 mg twice daily given for 4 days, has been proposed for the treatment of COVID-19 infection based on anin vitro study of projection of optimizing dose design of HCQ.
A combination of HCQ and azithromycin showed higher efficacy in viral elimination in a small French study. The study by Gautret et al. had some major limitations. The primary endpoint of the study was viral clearance by nasopharyngeal swab and not a clinical improvement. The sample size was not met, 12% of patients were excluded after recruitment, and all of them were from the HCQ group. Fifty percent of the patients were subsequently sent to the intensive care unit due to the worsening of the disease, and one of them died before the completion of the study. Seventeen percent of patients were asymptomatic, and 61% had only upper respiratory tract symptoms, which are indicative of milder disease subgroups. Further, the mean age was much lower in the study group compared to the control group, which must have skewed the data.
HCQ and chloroquine by having cellular effects such as lysosomal stability, increasing intracellular pH, and preventing antigen processing and presentation to T-cells can attenuate cytokine storm. In addition, they inhibit receptor binding and membrane fusion required for viral entry into cells. Multiple trials are currently underway evaluating the role of HCQ in prophylaxis and mild COVID-19 disease. A randomized, open-label clinical trial (NCT042261517) conducted at Shanghai Public Health Clinical Centre on efficacy and safety of HCQ for the treatment of pneumonia in COVID-19 showed that in 30 patients with mild disease, 93% in the placebo group and 87% in the HCQ group had viral clearance within 7 days ([unpublished data], [Booth B (March 24, 2020). In mild COVID-19 patients, placebo was similarly effective to HCQ in viral clearance, Twitter]). Another double-blinded RCT evaluated the efficacy of HCQ in COVID-19 treatment and showed promising results in terms of significant reduction of time to clinical recovery and pneumonia resolution. However, the main limitations of the study were the recruitment of mild cases and no estimation of the baseline viral load.
The National Taskforce for COVID-19 recommends the use of HCQ for prophylaxis of COVID-19 infection for asymptomatic healthcare workers involved in the care of suspected or confirmed cases and asymptomatic household contacts of laboratory-confirmed cases. The recommended prophylactic dose for asymptomatic healthcare workers is 400 mg twice daily on day 1, followed by 400 mg once weekly for the next 7 weeks. The dosage for asymptomatic household contacts is 400 mg twice daily on day 1, followed by 400 mg once weekly for the next 3 weeks. However, a previous randomized trial showed that chloroquine did not prevent influenza infections. Thus, extrapolation of any data into community use for COVID-19 prevention and prophylaxis is currently dubious.
In another study, HCQ use in SLE patients was shown to reduce the risk of infections; however, its role as a prophylactic agent in COVID-19 has been challenged., The current ongoing trials on HCQ in COVID-19 are listed in [Table 1].
|Table 1: Ongoing studies evaluating the role of hydroxychloroquine in treatment or prevention of Coronavirus disease 19 infection|
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A multicenter, open-label trial (NCT 04317092-TOCIVID 19) is underway recruiting patients with severe COVID-19 pneumonia being treated with tocilizumab, humanized monoclonal antibody against IL6 receptor, at a dose of 8 mg/kg (maximum of 800 mg). The primary endpoint is the 1-month mortality rate. Data from Anhui, China, showed that patients with severe or critical COVID-19 treated with tocilizumab became afebrile on the 1st day and other symptoms also improved remarkably. Seventy-five percent had reduced oxygen requirements, 90.5% showed a reduction in lung opacities, 52.6% had normalization of peripheral lymphocyte counts on the 5th day of treatment, and 84.2% had a significant decrease in CRP levels. Ninety percent of patients have been discharged, on an average of 13.5 days after treatment with tocilizumab. At this critical juncture, when we lack any proven treatment for this virus, a subgroup of patients with severe COVID-19 infection and elevated IL-6 levels or other features, suggesting secondary macrophage activation syndrome, may be considered for a therapeutic trial of tocilizumab. A trail of another human monoclonal antibody against IL-6 receptor, sarilumab, is also being carried out. The various ongoing trials evaluating the role of IL6 blockers are shown in [Table 2].
|Table 2: Ongoing studies evaluating the role of different IL-6 inhibitors in coronavirus disease-19|
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Another class of anti-rheumatic drugs under trial for COVID-19 infection is JAK inhibitors. They inhibit clathrin-mediated endocytosis and viral infection of the cells. They target members of numb-associated kinase family (NAK) – AAK1 and GAK – involved in viral infections. Baricitinib is identified as a NAK inhibitor, with particular potency for AAK1. Simultaneous inhibition of JAK-STAT signaling and NAK can be highly beneficial in COVID-19 infection, given the cytokine storm typically observed in these patients. Tofacitinib, on the other hand, has no AAK1 inhibitory actions. Compared to other JAK inhibitors such as ruxolitinib or fedratinib, which have to be given in higher dose for antiviral effects than the currently used doses, baricitinib can be used in once-daily dosing for 7–14 days. Baricitinib can also be combined with presently used directly acting antivirals (lopinavir/ritonavir and remdesivir) as it has minimal drug interactions. The potential utility of this drug will become clearer as clinical data emerge regarding this [Table 3].
|Table 3: Ongoing studies evaluating the role of small molecules in coronavirus disease-19|
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During previous outbreaks of SARS, MERS, Ebola virus, or H1N1 pandemic 2009, convalescent plasma use showed reduced mortality and shorter hospital stay. Convalescent plasma has antibodies that reduce viremia. Similar to above, convalescent plasma from recovered patients with COVID-19 may be used to treat severe or critical patients with this novel virus.
The current guidelines and evidence do not support the use of systemic corticosteroids in COVID-19. From previous experience in SARS, MERS, RSV, or influenza, corticosteroids increased mortality, increased infection rates, and impaired viral clearance. Hence, in the current pandemic as well, its use may be detrimental. The various ongoing trials evaluating the role of different anti-inflammatory agents such as systemic corticosteroids, NSAIDs, and colchicine are shown in [Table 4].
|Table 4: Ongoing studies evaluating the role of different anti-inflammatory agents in coronavirus disease-19|
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Considering the cytokine storm associated with COVID-19 infection and severity determined by the same, other potential anti-cytokine drugs currently under trial are anakinra (IL-1 antagonist) and emapalumab (immunoglobulin G1 antibody against interferon gamma).
To conclude, we wish to state that in the present COVID-19 era, the risk stratification of rheumatology patients can help in therapeutic decision-making such as self-isolation, continuation, or initiation of immunosuppressive therapy. Various studies have been initiated on the role of different anti-rheumatic drugs in COVID-19, and their place in its management would only become clear once the results of those studies become available. The treatment interruption should not be made in fear, and there should be shared decision-making in consultation with the patient.
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Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4]