Benefits and adverse effects of hydroxychloroquine, methotrexate and colchicine: searching for repurposable drug candidates

Abstract

Repurposing of antirheumatic drugs has garnered global attention. The aim of this article is to overview available evidence on the use of widely used antirheumatic drugs hydroxychloroquine, methotrexate and colchicine for additional indications. Hydroxychloroquine has endothelial stabilizing and anti-thrombotic effects. Its use has been explored as an adjunctive therapy in refractory thrombosis in antiphospholipid syndrome. It may also prevent recurrent pregnancy losses in the absence of antiphospholipid antibodies. Hydroxychloroquine favourably modulates atherogenic lipid and glycaemic profiles. Methotrexate has been tried for modulation of cardiovascular events in non-rheumatic clinical conditions, although a large clinical trial failed to demonstrate a benefit. Colchicine has been shown to successfully reduce the risk of recurrent cardiovascular events in a large multicentric trial. Potential antifibrotic effects of colchicine require further exploration. Hydroxychloroquine, methotrexate and colchicine are also being tried at different stages of the ongoing Coronavirus Disease 19 (COVID-19) pandemic for prophylaxis and treatment. While the use of these agents is being diversified, their adverse effects should be timely diagnosed and prevented. Hydroxychloroquine can cause retinopathy and rarely cardiac and auditory toxicity, retinopathy being dose and time dependent. Methotrexate can cause transaminitis, cytopenias and renal failure, particularly in acute overdoses. Colchicine can rarely cause myopathies, cardiomyopathy, cytopenias and transaminitis. Strong evidence is warranted to keep balance between benefits of repurposing these old antirheumatic drugs and risk of their adverse effects.

Public interest in rheumatic diseases and rheumatologist in the United States during the COVID-19 pandemic: evidence from Google Trends

“…It is interesting to note that there was no significant difference in relative search volume of the term "rheumatologist" between May 10 and July 4, 2020 compared to similar periods in 2016-2019; however, a statistically significant increase was seen in the July 5-August 29, 2020 period. This finding that indicates the increased need for rheumatologists during the COVID-19 pandemic may be attributable to two factors: (a) patients with a rheumatic disease and/or receiving immunosuppressive treatments wanted to consult rheumatologists on their disease/treatments [30]; (b) patients consult rheumatologists on properties of several anti-inflammatory and immunomodulatory drugs that are being used in the treatment of COVID-19 because rheumatologists are experts in the use of these drugs [1,7]. Rheumatic patients may be at a higher risk of receiving COVID infection with worse outcomes, as many of them tend to be susceptible from their underlying rheumatic disease or immunocompromised due to their treatment [9][10][11][12][13][14][15][16].…”

“…Thus, this pandemic has put great responsibility on the shoulders of the rheumatologists for caring for this vulnerable patient group. In addition, considerable knowledge of rheumatologists and immunologists on the management of patients with pathological immune responses coupled with their substantial clinical experiences with many of the drugs that are currently being tested as potential COVID-19 treatment has led to rheumatologists and immunologists being placed right in the frontlines in facing COVID-19 [1][2][3][4][6][7][8]. All these demonstrate that the rheumatologists and immunologists have an indispensable role during the COVID-19 pandemic.…”

“…Rheumatologists and immunologists have substantial expertise in the pathogenesis of the immune response, the impact of inflammation, and their treatments [1][2][3][4]. Several immunomodulatory and antiinflammatory drugs (e.g., hydroxychloroquine, colchicine, tocilizumab, anakinra) have been used for COVID-19 when scientists are in search of a possible treatment for this novel virus and a resultant inflammatory response [1][2][3][4][6][7][8]. Since rheumatologists have substantial knowledge in the benefits and adverse effects of these drugs as well, rheumatologists are playing a significant role in this pandemic.…”

Colchicine as an adjunct to heparin for prophylaxis of venous thromboembolism in patients with COVID-19

“…The comprehensive review by Misra et al [ 1 ] on the effects of antirheumatic drugs, including hydroxychloroquine, methotrexate and colchicine, in patients with coronavirus disease 2019 (COVID-19), along with discussion on their positive and negative sides to guide repurposing of these antirheumatic drugs against COVID-19, is commendable. Particularly, we read with interest the authors’ viewpoints regarding the potential therapeutic roles of colchicine in patients with COVID-19, and we would like to complement to their discussion on colchicine based on recent understandings on the pathophysiology of COVID-19.…”

“…Since NETs contribute to immunothrombosis in patients with COVID-19, especially those with severe disease, anti-NETs therapeutics may be useful as an adjunct to prophylactic-dose low molecular weight heparins for the prevention of VTE in this patient population. Colchicine has emerged as a potential treatment for patients with COVID-19 as discussed by Misra et al [ 1 ], and interestingly colchicine could suppress NET formation [ 6 ]. Colchicine stabilizes the cytoskeleton, thereby attenuating chromatin swelling and subsequent NET release from neutrophils.…”