Treating COVID-19 or Rheumatoid Arthritis? Exploring Proposed Drug Therapy, Safety Concerns

The coronavirus disease 2019 (COVID-19) pandemic, which has infected many individuals in a short timeframe, has pressured researchers to scramble to identify and/or develop efficacious treatments. The need for these treatments has prompted the FDA to authorize Emergency Use Authorization (EUA) to allow some currently marketed drugs to be used experimentally in severe cases.¹

­COVID-19 is transmitted through respiratory droplets. In severe cases, the virus can wreak havoc on the lungs and may lead to the development of pneumonia or the potentially fatal condition acute respiratory distress syndrome.² Consequently, due to the toll the disease takes on the body, some patients are left unable to fight the infection. Upon discovering the effects on the lung, researchers determined the infection that leads to COVID-19 to be severe acute respiratory syndrome-related coronavirus (SARS-COV-2).²

This viral infection in the lungs leads to the excessive production of cytokines, causing a phenomenon known as a cytokine storm. This storm begins with the release of interleukin-1 (IL-1), along with other cytokines, within minutes to hours of infection. The immune system is then further stimulated by interleukin-6 (IL-6) as it attempts to eradicate the infection.

Finally, interleukin-10 (IL-10) production is stimulated to tone down the immune response. However, at this stage, the cytokine storm has already damaged the lung tissue and must be repaired in order to help eradicate the infection.

The damage is repaired by producing new collagen tissue. Meanwhile, the infection may still be worsening throughout the body and potentiating further complications, sepsis, and possible mortality.³ With the potentially severe consequences of COVID-19 infection, it is vital to identify treatment options that are effective while minimizing harm from potential adverse drug reactions.

As scientists fervently research treatments, one avenue of exploration has been repurposing existing drugs as COVID-19 treatments. Examples of repurposed drugs are those commonly indicated for autoimmune diseases such as rheumatoid arthritis (RA). However, what characteristics of RA treatments possibly connect to COVID-19 treatment?

RA is an autoimmune disease wherein treatments are targeted to suppress the immune system to preserve functional use and reduce pain in patients with the disease. The mainstays of therapy include drugs that inhibit the immune system mainly through actions on cytokines and T-cells. However, some drugs commonly used to treat RA can also be utilized in other conditions.

For example, hydroxychloroquine, which reduces cytokine production is also used for malaria prophylaxis but relies on a different mechanism of action for this purpose. Although hydroxychloroquine was granted EUA for treating COVID-19¹ in March 2020, some studies have found cause for safety concerns, including increased risk of death.⁴ Studies are ongoing to to determine the efficacy and safety of the drug for COVID-19. In RA treatment, hydroxychloroquine’s efficacy may be at least in part secondary its effects on cytokine production. Furthermore, for COVID-19, hydroxychloroquine may inhibit the virus’ ability to bind/penetrate respiratory cells.⁵

Many other drugs that also treat autoimmune diseases (including RA agents) have been proposed but require more clinical data.^6,7

When considering these drugs as possible COVID-19 treatments, the safety and common adverse effects of these proposed medications should be considered and weighed carefully (Table). At the time of publication, only hydroxychloroquine and remdesivir (which is not indicated for RA) had “compassionate use” status. This use brings an enhanced focus on drug safety profiles to light.

Perhaps the most concerning safety issue associated with hydroxychloroquine treatment is potential cardiac toxicity, specifically with noted changes in ECG readings leading to some patients discontinuing drug therapy.⁸ Another noted safety concern is retinal toxicity.

This effect can occur with both acute and long-term use but is rare in the acute phase (<1%). The risk of retinal toxicity, however, is increased in doses above 5 mg/kg of actual body weight daily or with extended therapies. Consequently, ocular examinations are recommended prior to initiation of chronic therapy but may not be meaningful or feasible for COVID-19 patients requiring swift intervention.⁹

Table 1: Summary of RA Agents Proposed as COVID-19 Treatments Potential COVID-19 Therapy

Potential COVID-19 Therapy

Mechanism of Action

Adverse Drug Reactions

Monitoring

Hydroxycloroquine

RA: reduce cytokine production

SARS-CoV-2: binds to Salic acid residues and gangliosides to prevent viral attachment and entry into the cell⁴

Cardiomyopathy

Neuropathy

QTc prolongation

Retinal toxicity

Hypoglycemia

Neuropsychiatric symptoms^10,11

EKG

Muscle strength

Deep Tendon Reflexes

Eye examination within first year of use and at least every 5 years without risk factors

Blood glucose if symptomatic

Baseline G6PD deficiency¹⁰

Tocilizumab

IL-6 inhibitor

Injection site reactions

Increased risk of infections

Neutropenia

Thrombocytopenia Hepatotoxicity¹¹

CBC

LFTs¹²

Sarilumab

IL-6 inhibitor

Injection site reactions

Increased risk of infections

Osteoarthritis

Neutropenia

Thrombocytopenia Atrial Fibrillation¹²

CBC

LFTs¹³

Anakinra

IL-1 inhibitor

Injection site reactions

Increased risk of infection

Neutropenia

Malignancy

Hypersensitivity

Immunogenicity¹⁴

CBC¹⁴

Corticosteroids

Reduces inflammatory mediators

Immunosuppression

Hypertension

Hypoglycemia

Adrenal suppression

Myopathy

Blood pressure

Weight

Blood glucose

Electrolytes

Bone mineral density

HPA axis suppression

CBC¹⁶

Each RA medication listed in the table has a risk of immunosuppression due to the nature of their mechanisms of action. For example, hydroxychloroquine inhibits cytokines and Toll-like receptor signaling while also reducing CD154 expression when used in RA.¹⁴

For SARS-CoV-19 on the other hand, hydroxychloroquine’s potentially effective actions include binding to Salic acid residues and gangliosides. This action prevents the virus from attaching to these sites and getting into the cell in order to replicate.³

The other medications listed in the table (excluding corticosteroids) block a specific aspect of interleukins, which are other immune system regulators like cytokines. Tocilizumab and sarilumab are both IL-6 inhibitors while anakinra is an IL-1 inhibitor.

These affect the immune process at a certain location without blocking the entire immune system and help limit the cytokine storm. Tocilizumab has an indication for the treatment of cytokine release syndrome due to chimeric antigen receptor-T cell therapy in severe or life-threatening cases. Meanwhile corticosteroids inhibit inflammatory mediators.

In summary, although each medication exerts its effects differently, they all work in some way to inhibit a portion of the immune response that could present a risk of secondary infections in those with already taxed immune systems, such as COVID-19 patients.^10-15

Upon inspection of the medications considered to potentially treat COVID-19, common goals seem to be a reduction in cytokine storm by either inhibiting interleukins in the storm itself or inhibiting the entry of the virus into cells. With the decrease in the cytokine storm comes the reduction of the damage done to the lungs by the immune system and possibly decreased clinical worsening, sepsis, and ultimate mortality.

Continued research is drastically needed in this area to gain insight on an effective strategy to combat COVID-19. Providers must also continue to consider potential safety repercussions of treatment options, particularly the safety of proposed immunosuppressive agents.

REFERENCES

• Rome BN, Avorn J. Drug Evaluation during the COVID-19 Pandemic. N Engl J Med. 2020. doi:10.1056/NEJMp2009457
• Mehta P, McAuley DF, Brown, M, Sanchez, E, Tattersall, RS, Manson, JJ. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet Digit Health. 2020; 395(10229): 1033-1034. doi:10.1016/S0140-6736(20)30628-0
• Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol. 2012;76(1):16-32
• Hippensteele A. Study: Use of Hydroxychloroquine in Patients With COVID-19 Increases Mortality. Pharmacy Times website. https://www.pharmacytimes.com/news/study-use-of-hydroxychloroquine-in-patients-with-covid-19-increases-mortality Published April 22, 2020. Accessed June 3, 2020.
• Fantini J, Di Scalia C, Chahinian H, Yahi N. Structural and molecular modeling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents. 2020; [epub ahead of print]. Accessed 2020 Apr 23.
• Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020. doi:10.1001/jama.2020.6019
• Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clin Immunol. 2020; 214(108393) doi:10.1016/j.clim.2020.108393
• Mahevas M, Tran V-T, Roumier, M, et. al. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial. medRxiv. 2020. doi:10.1101/2020.04.10.20060699.
• Marmor MF, Kellner U, Lai T et al. 2016 AAO guidelines on screening for chloroquine and hydroxychlororquine retinopathy. Published 2016 Mar 16.
• Plaquenil hydroxychloroquine sulfate tablets, USP. accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf. Accessed Apr 2020
• Juurlink, D. Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection. CMAJ. Doi: 10.1503/cmaj.200528; early-release April 8 2020. Accessed April 15, 2020
• Schiff MH, Kremer JM, Jahreis A, Vernon E, Issacs JD, van Vollenhoven RF. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 2011; 13(5):R141. Accessed 2020 Apr 15.
• Fleischmann R, Genovese MC, Lin Y, et. Al. Long-term safety of sarilumab in rheumatoid arthritits: an integrated analysis with up to 7 years’ followup. Rheumatology (Oxford). 2020; 59(2):292-302. Accessed 2020 Apr 15.
• Kineret (anakinra) for injection, for subcutaneous use. FDA. Accessdata.fda.gov/drugsatfda_docs/label/2012/103950s5136lbl.pdf. Accessed 2020 Apr 15.
• Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;(16):155-166.
• Prednisone. In: Lexi-Drugs [online database]. Hudson, OH. Accessed 2020 May 8.