Anti-Rheumatic Therapies for COVID-19 Infection Save

Since the onset of the COVID-19 pandemic numerous anti-rheumatic therapies have been proposed as being potentially beneficial. The mechanistic effects of these agents, either presumed antiviral, anti-inflammatory and anti-thrombotic effects, may benefit mitigate the damage seen with COVID-19 infection.

This review will examine the potential benefits and existing evidence for treating suspected or proven COVID-19 infection with antimalarials, inhibitors of interleukin-6 (IL-6) or interleukin-1 (IL-1) Janus kinase (JAK) inhibitors, TNF inhibitors or colchicine. There are many other antirheumatic and immunosuppressive therapies that are in clinical trials that will not be reviewed here including IVIG, rituximab, calcineurin inhibitors (sirolimus, etc.), apremilast, emapalumab (anti-IFN gamma), etc.

Anti-malarials

In early March 2020m hydroxychloroquine (HCQ) and chloroquine (CQ) were promulgated as a potentially beneficial because of their use with malaria and clinical trials treating other viral infections. However, HCQ and CQ have failed in other viral infections including influenza, dengue, chikungunya, Ebola and HIV.  Nonetheless, the FDA green-lighted early studies of antimalarials by issuing an “emergency use authorization” for both chloroquine and hydroxychloroquine on March 31st. Contemporaneously COVID treatment guidelines from the American College of Rheumatology (ACR) and NIH suggested that patients receiving chronic HCQ for a rheumatic condition should continue on HCQ and that if a patient had a presumed or proven COVID-19 this agent could be continued.

Between March and June 2020, there were numerous observational and cohort reports demonstrating either no evidence of a protective effect and some showed either more deaths or poorer outcomes when hydroxychloroquine was used. Many of these death and poor outcomes could be attributed to only the sickest of patients being put on this speculative intervention.  In fact there were very few reports of HCQ or CQ cardiotoxicity or arrhythmias, including QT (QTc) prolongation or torsades de pointes. With  mounting evidence of inappropriate HCQ used by the public, the FDA and Health Canada issued safety warnings against the routine or prophylactic use of anti-malarial agents in COVID-19, especially for those not hospitalized or participating in clinical trials. By mid-June 2020 growing equivocal or negative evidence resulted in: 1) FDA withdrawal of its “emergency use authorization”; 2) WHO suspending its large “SOLIDARITY” trial of hydroxychloroquine in COVID-19; and 3) the NIH and numerous sponsors also suspending their HCQ trials.

More recently, a NEJM article showed that when HCQ was ineffective at prophylaxis. When given to 812 COVID exposed asymptomatic persons, it was not as shown to reduce COVID-19 infections.(1)

JAK Inhibition

Janus kinase (JAK) inhibitors are understudy in COVID-19 as research showing that baricitinib inhibits viral endocytosis via inhibitory effects on AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK). Moreover, JAK inhibitors are known to substantially downregulate inflammation by blocking cytokine (e.g., IL-6 and interferon) signaling.  Hence there may be a rationale for either the early (antiviral) or late (anti-inflammatory) use of baricitinib or other JAK inhibitors currently in clinical trials (tofacitinib, ruxolitinib, etc.). Baricitinib has been studied in a small cohort of 12 patients and when given with antiviral therapy for 2 weeks, those treated with baricitinib had more improvements in CRP levels, lymphopenia, ICU admissions and hospital discharges, compared to those who not receive baricitinib (2).

Interleukin-6 Inhibition

IL-6 has been shown to be a key regulator of the “cytokine release syndrome” seen with CART-cell therapy in acute leukemia. Such patients are at high risk for grade 3 and 4 cytokine release syndrome (CRS) with fever capillary leak, hypotension and organ damage. When these patients were treated with intravenous tocilizumab (an IL-6 inhibitor) the vast majority showed substantial improvement. 

COVID patients are at morbid and mortal risk for the cytokine storm syndrome complication and IL-6 inhibition has been amongst the many agents under study for this complication and in severe COVID pneumonia as well.  Tocilizumab is currently approved for use in rheumatoid arthritis, juvenile arthritis, Still's disease, giant cell arteritis and the cytokine release syndrome (with CAR-T cell therapy). The usual dose is 4 to 8 mg/kg given IV, but in extreme inflammation (e.g., Still’s disease, CRS) most use either 8 to 12 mg/kg as a single dose that can be repeated in two weeks in those who are gravely ill. Common complications of IL-6 inhibitors would include a slight increase in serious infections, hepatic enzyme elevations, hyperlipidemia, neutropenia and a very low risk of GI perforation (0.26/100 patient-years exposure).

Most of the existing evidence is uncontrolled observational or cohort studies that have not been peer-reviewed. Nonetheless thus far, most of these trials have shown favorable outcomes when given to patients with severe COVID-19 infection. There are numerous trials ongoing on several different IL-6 inhibitors including tocilizumab, sarilumab and sirukumab, with most available evidence reported for tocilizumab. The uncontrolled clinical trials thus far have shown improvements in those receiving high doses sarilumab or tocilizumab. These trials were largely done in COVID pneumonia patients or those with severe disease and impending respiratory failure. IL-6 inhibition reduced the need for mechanical ventilation and/or lowered death rates in these studies. Although IL-6 inhibition is given to either treat or prevent cytokine storm syndrome, there are no current results showing its efficacy in patients with cytokine storm and severe COVID-19 infection (3).

Interleukin-1 Inhibition                   

There are numerous IL-1 inhibitors in COVID clinical trials, including the short-acting anakinra, and the longer acting canakinumab. Anakinra has been in 2 clinical studies. In one it was given as 100 mg twice a day subcutaneously (or 5 mg/kg twice a day intravenously) to 29 COVID (+) patients with non-ICU ARDS and high inflammatory markers (CRP or ferritin). Those on anakinra had better survival (90% vs. 56%; p=0·009), better correction of CRP and respiratory function (72% vs 50%) and compared to non-anakinra patients after 3 weeks of observation. Another retrospective series of 11 severe COVID-19 treated with anakinra showed that if given within the first 36 hours there was no death or requirement for mechanical ventilation (7 patients) compared to 2/4 patients who died or required ventilation when receiving after 4 days or more. Clinical trials are canakinumab are pending (4).

Dexamethasone

Glucocorticoid use is potentially life-saving or adds to complications in such severely ill patients.  The NIH consensus guidelines on the treatment of COVID-19 recommended against the use of systemic corticosteroids in mechanically ventilated patients without evidence of acute respiratory distress syndrome (ARDS). And for those with ARDS, they cannot recommend for or against the use of systemic corticosteroids.  Last month, preliminary results were released from the RECOVERY (trial) Collaborative Group from Oxford, showed that dexamethasone (DEX), was capable of reducing mortality rates by 30%. This trial was called a “major breakthrough” by some and viewed with skepticism by others. The study looked at to hospitalized, severely ill, COVID-19 patients and compared outcomes in 2100 dexamethasone treated patients with 4,300 patients on placebo. The 28 day mortality rate was 21.6% with DEX and 24.6% with usual care (p<0.001). There were also fewer mechanical ventilations (5.2% vs 7.1%; p=-.021) and more hospital discharges at day 28 (64.6% vs. 61.1%; p=0.002).   

Colchicine

Colchicine is currently used to treat gout, pseudogout, familial Mediterranean fever and pericarditis. It is thought to work by inhibition of microtubules, neutrophil chemotaxis and inflammasome activation via NALP3. The agent has been proposed as an early intervention and is understudy by the Montreal Heart Institute (along with UCSF and NYU) in a 6000 patient trial. A recent JAMA report of the GRECCO study showed in an open-label clinical trial of 105 patients, those treated with colchicine had less clinical deterioration without significant changes in biomarkers, such as high-sensitivity cardiac troponin and C-reactive protein (5).

References

Boulware DR, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020 Jun 3 PMID: 3249229

Richardson P,  et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020 Feb 15;395(10223):e30-e31

Cavalli G, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020 Jun;2(6):e325-e331

Deftereos SG, et al. Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.   JAMA Netw Open. 2020;3(6):e2013136.