Cytokine storm release syndrome and the prospects for immunotherapy with COVID-19, part 4: The role of JAK inhibition

Leonard H. Calabrese; Tiphaine Lenfant; Cassandra Calabrese

doi:10.3949/ccjm.87a.ccc060

View current version of this article

Article Figures & Data

Figures

Tables

Download figure
Open in new tab
Download powerpoint
Figure 1
Course of COVID-19 infection: A paradigm for therapy.

Tables

Figures

View popup

TABLE 1

Cytokines of interest in COVID-19 involving the JAK-STAT pathway

Family	Type I cytokines	Signaling JAKs	Signaling STATs	Hyperinflammation	Viral clearance	Safety concerns
Common β-χ	GM-CSF	JAK2	3+5	X
Common ɣ-c	IL-15	JAK1, JAK3	3+5		X
	IL-21	JAK1, JAK3	1+3+5		X
	IL-13	JAK1, JAK3, TYK2	6	X
	IL-2	JAK1, JAK3	3+5	X
	IL-4	JAK1, JAK3	6	X
	IL-7	JAK1, JAK3	3+5	X
	IL-9	JAK1, JAK3	1+3+5	X
Dimeric	IL-12	JAK2, TYK2	4		X
gp130	IL-6	JAK1, JAK2, TYK2	1+3	X
Hormone-like	G-CSF	JAK2	5	X
	Type II cytokines
IFN	IFN α/β	JAK1, TYK2	1+2+3+4+5	X	X	X
	IFN ɣ	JAK1, TYK2	1	X	X	X
IL-10	IL-10	JAK1, JAK2, TYK2	1+3+5	X

G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrχχophage colony-stimulating factor; IFN = interferon; IL = interleukin; JAK = Janus kinase; STAT = signal transducers and activators of transcription; TYK = tyrosine kinase

View popup

TABLE 2

Clinical trials involving JAK-inhibitors in COVID-19 (7/20/2020)

JAK-inhibitor	Phase 2	Phase 3	Phase 4
Baricitinib (12 total)	NCT04373044	NCT04340232	NCT04390464
	NCT04393051	NCT04358614
	NCT04346147	NCT04320277
	NCT04321993	NCT04421027
	NCT04399798	NCT04401579
		NCT04345289

Ruxolitinib (14 total)	NCT04334044	NCT04348071
	NCT04414098	NCT04477993
	NCT04354714	NCT04377620
	NCT04366232	NCT04362137
	NCT04338958	NCT04424056
	NCT04374149
	NCT04359290
	NCT04403243
	NCT04348695

Tofacitinib (5 total)	NCT04412252
	NCT04415151
	NCT04469114
	NCT04390061
	NCT04332042

Source: www.clinicaltrials.gov

View popup

TABLE 3

Current JAK inhibitors

Targets	Drug	Indication and dosage	Warnings and side effects
JAK1, JAK2	Baricitinib (Olumiant)	Rheumatoid arthritis: oral 2 mg once daily	Warnings: Do not initiate in case of anemia < 8 g/dL, lymphopenia < 500/mm³, severe hepatic impairment, moderate or severe renal impairment Side effects: Infectious (tuberculosis), hematologic (lymphoma), thrombosis, gastrointestinal perforation

JAK1, JAK2	Ruxolitinib (Jakafi)	Myelofibrosis: 5 to 20 mg orally twice daily depending on platelets count Polycythemia vera: 10 mg orally twice daily Acute graft-vs-host disease: 5 mg orally twice daily	Warnings: Adjustment on renal/hepatic impairment and platelet count Side effects: Hematologic (pancytopenia, thrombocytopenia, anemia, neutropenia), infectious (herpes zoster, opportunistic infections), oncologic (non- melanoma skin cancer), metabolic (weight gain, hypercholesterolemia), other (bruising, dizziness, headaches)

JAK3 (and JAK1, JAK2)	Tofacitinib (Xeljanz)	Rheumatoid arthritis and psoriatic arthritis: orally, 5 mg twice daily or 11 mg once daily Ulcerative colitis: orally, 10 mg twice daily	Warnings: Avoid in patients at increased risk of thrombosis; avoid the combination with methotrexate or other disease-modifying anti-rheumatic drug or immunosuppressant; do not initiate if lymphocytes < 500/mm³, neutrophils < 1,000/mm³, or hemoglobin < 9 g/dL; adjust on renal or hepatic impairment Side effects: Thrombosis, infections (tuberculosis, opportunistic infections, herpes zoster), malignancy (lymphoma, skin cancer), gastrointestinal perforation, hematologic (anemia, lymphopenia, neutropenia)