Repurposing anti-rheumatic drugs in COVID

Dr. Sabarinath Mahadevan*

Rheumatologist, Kauvery Hospital, Salem, India

Background

The pandemic has taught us many things. Right from the importance of being together as a family, supporting fellow humans and be grateful for each moment gifted to us, we have learnt it all. The medical community has witnessed how a collaborative team work could enable us to overcome a novel virus and gruesome pandemic. The scientific forums, journals and websites experienced a flood of research related to COVID, that almost we need to keep ourselves updated every day. To me, as a clinical immunologist and rheumatologist it is a moment of reckoning to see a medical knot getting untangled very evidently. In most human afflictions, say infections like dengue or COVID, autoimmune diseases, cancer etc the immune system has a pivotal role to play. The outcome of these diseases may be altered by modulating the same. The treatment of infections has long been focused on elimination of offending microbes thereby helping or augmenting the body immune defense in doing the same. Very rarely it is comprehended, that the immune system which provides the defense, also does the offense to our body. More than any complex theoretical immunological signal transduction pathways, the therapeutic armamentarium of COVID has spelled it out clearly. In certain scenarios like COVID, silencing or modulating our immune system may indeed be useful. Generally considered as a drug contraindicated in infections, steroids has reduced the mortality of patients with severe COVID infections. The text below summarizes the drugs which are originally used in immuno- modulation of autoimmune diseases and are currently studied in improving the outcomes of COVID infections, along with their important evidences.

Hydroxychloroquine

The drug has seen a complete turn from scarcely available to recommendations against its use in COVID. The in vitro lysomatrophic action of chloroquine in increasing pH of endosomes and preventing viral replication did not work in vivo. The RECOVERY and SOLIDARITY trail have sent this drug back to the pavilion.

Colchine

As an anti-inflammatory drug in gout and auto-inflammatory syndromes, colchine is known to inhibit neutrophil chemotaxis, inflammasome assembly and interferon 1 beta production. Though a slight reduction in hospitalization of subset of outpatients is documented (subgroup with nasopharyngeal RTPCR positive) in COLCORONA trial, the drug didnâ€™t achieve its primary endpoint (composite of hospitalization or death by day30). There are no benefits of its use in hospitalized patients either (RECOVERY trial).

Toclizumab

The IL-6 receptor blockers toclizumab and sarilumab has shown modest use in COVID patients who are critically ill. IL-6 is a prime proinflammatory cytokine released by variety of immune cells and non-immune cells like bronchial epithelium. The levels of IL-6 correlate with CRP, Ferritin and D- dimer. Various trials have proven its role in critically ill patients requiring oxygen, when used along with steroids. We have more evidence for toclizumab compared to sarilumab. Siltuximab (IL-6 BLOCKER) is not currently approved for use outside clinical trials in COVID.

Trial	Inclusion population	Primary outcome/interpretation
RECOVERY	SPO2 < 92% or requiring supplemental oxygen	All-cause mortality on day 28 is lower in toclizumab arm compared to routine care arm.
REMAP-CAP	COVID 19 suspect or confirmed requiring ventilator or cardiovascular support.	Use in ICU patients within 24 h of admission is associated with better survival and shorter duration of requirement of organ support in toclizumab/sarilumab.
COVACTA	PCR confirmed COVID with hypoxemia and bilateral chest infiltrates.	No difference between toclizumab and placebo in primary outcome (ordinal scale of day 28 clinical status). Patient in toclizumab arm have shorter ICU stay and required shorter time to recovery.
EMPPACTA	PCR confirmed COVID pneumonia. Patients requiring ventilation are excluded.	Proportion of patients who required ECMO, IMV or died by day 28 is more in placebo (19%) compared to toclizumab arm (12%) (p = 0.04).
BACCbay	Laboratory confirmed COVID with 2 out of 3 of fever/oxygen requirement/infiltrates with one elevated lab parameter. (CRP/LDH/ferritin/D- dimer)	No difference between toclizumab and placebo in reduction of 28-day mortality or intubation or reduction of oxygen support or prevention of clinical worsening. The lack of significant response is attributed to low use of concomitant steroids.

JAK Inhibitors

JAK-STAT signal transduction is a vital intracellular pathway for multiple cytokines. Blocking of this pathway would therefore have the potential to reduce the impact of cytokine storm in COVID. There are many JAK inhibitors based in their selectivity for JAK1, JAK2, JAK3 or TYK-2. Baricitnib acts predominantly on JAK 1, 2 and tofacinitib on JAK 1, 3. Baricinib and ruxolitinib, in addition has anti-viral effects.

Trial	Inclusion population	Primary outcome/interpretation
ACTT-2	Hospitalized patients with COVID 19.	Baricitinib improves time to recovery when given in combination with remdesivir to hospitalized patients requiring supplemental oxygen but not mechanical ventilation. Steroids are not used as a standard treatment in this trail.
COV-BARRIER	COVID 19 pneumonia, not on mechanical ventilation and with atleast one elevated inflammatory marker.	No significant difference compared to placebo in proportion of patients who progressed to high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation or death by day 28. (27.8% baricitinib arm versus 30.5% placebo arm, P = 0.18). But significant reduction in baricitinib arm for secondary end point of day 28 all-cause mortality (8.1% baricinib arm vs 13.1% placebo arm). Baricinitb has additional survival benefits when used along with steroids (with or without remdesivir).
STOP-COVID	Hospitalized patients who are not mechanically ventilated. Patients are on background steroids.	Death or respiratory failure through day 28 is seen in 18.1% in tofacitinib arm compared to 29% of placebo arm.

IL-1 Inhibitors

IL-1 inhibitors are used in juvenile arthritis and various auto-inflammatory syndromes. It is released by multiple innate immune cells and damaged epithelium in COVID infection. The cytokine propagates downstream inflammation and drives the cytokine storm. Four important trials studied the use of IL-1 blockers in COVID. In SAVE-MORE trial which enrolled patients with moderate or severe COVID-19 pneumonia and elevated plasma-soluble urokinase plasminogen activator receptor (suPAR), use of anakinra (IL-1 receptor antagonist) reduced the clinical progression (primary end point of reduction in 11 point WHO clinical progression scale) in COVID compared to placebo. This study excluded patients who received invasive or non-invasive ventilation. CORIMUNO-ANA-1 trial which included hypoxemic patients is terminated prematurely due to lack of benefit. REMAP- CAP, an open label adaptive trial didnâ€™t find anakinra useful. Another RCT CAN-COVID, which studied canakinumab (IL-1 beta blocker) in hospitalized hypoxemic patients (but not on ventilator) found that canakinumab alone did not improve survival without invasive ventilation. Based on these data from these trials and as suPAR assay is not widely available, the use of these drugs is not approved outside clinical trial setting.

GM-CSF Inhibitors

Granulocyte macrophage colony stimulating factors is a growth factor and acts upstream in formation, activation of immune cells. Inhibition of this growth factor has the potential to modulate the immune mediated lung injury and cytokine storm. Though the study populations differed (room air vs oxygen), preliminary data on use of GM-CSF inhibitors like otilimab, mavrilimumab did not show improvement in survival compared to placebo. Currently these drugs are not used outside research settings.

Conclusion

To conclude, apart from steroids, immuno-modulation by IL-6 blockers and JAK inhibitors has a promising role in severe COVID 19 illness. As our understanding on the immunopathogenesis of disease and cytokine storm evolves, we may expect more immuno-modulators for use in COVID in future. As we venture into the use of these immuno-modulators in patients with severe infections, we may also need to be aware of the repercussions. Opportunistic infections, liver damage, cytopenias, venous thrombosis and gastro intestinal adverse effects are well known with these drugs, from its use in rheumatology practice. Choosing the right patient, optimal timing, dose, duration of therapy, supportive treatment, follow up care and family counseling must be given due importance.

Dr. Sabarinath Mahadevan

Rheumatologist

Repurposing anti-rheumatic drugs in COVID