Clofazimine is a rimophenazine dye originally used as an antitubercolar
agent after its first synthesis at Trinity College of Dublin, during
1954, by a group of scientist led by V. Barry. Only few years later it
was awarded for leprosy treatment by Y. T. Chang. With the following
years, also an anti-inflammatory effectiveness on erythema nodosum
leprosum was recognized (1 ). In the ‘70s therapeutical activity on
discoid lupus erythematosus and pyoderma gangrenosum were documented ( 2
).
Recent papers suggest interesting properties of modulation of the immune
responses: first by blockade of Kv 1.3 potassium channel, a voltage
dependent transmembrane domain first identified outside electrically
excitable tissue, for instance on macrophages and T lymphocytes; in the
latters it carries on a critical role for the subset of “effector
memory” ( CD4+ CD62L lo CD44hi) when blocked, downgrading such function
in severe, inflammatory diseases, and expanding, instead, “central
memory” population, ( CD4+ CD 62Lhi CD44hi), ( 3, 4 ).
The induction of long living, antigen specific “central memory” T
cells is supported of an efficient and long lasting action against
bacterial and viruses, whereas a quick overload of T cells “effector
memory” may be detrimental for the organism because instauration of a
more severe inflammatory condition during an infectious disease, like
tuberculosis and SARS syndromes ( 5 ).
Clofazimine is electively accumulated in macrophages , forming crystal-
like inclusions, with effects on the microenvironment of phagosomes,
resulting in a contrast of bacterial replication, also grounded on an
inhibitory action of acid sphingomyelinase, that hinder the ceramide
accumulation induced by intracellular pathogens, and restore the
autophagic clearance of intracellular pathogens (6 ). On the other hand,
in models of bacterial pathogen killing also an apoptosis inducing
activity in macrophages may be promoted ( 7 ). Inside these cells, the
drug in the inclusions alters immune signaling response pathways, like
Toll like receptor ( TLR) ligation and then expression, decreasing of
NF-kB activation and Tumor necrosis factor ( TNF) production, enhancing
the interleukin-1 receptor antagonist ( IL-1RA) production .
Clofazimine might be able to promote antigen specific Th17 cascade in
lymphocytes “central memory”, acting as a “self propelled vaccine”
in infection and cancer; however an effectiveness to inhibit
TCR-mediated IL-2 production was also confirmed in cell lines, resulting
in an immunomodulatory effect .
In human immunodeficiency virus/AIDS clofazimine may provide some
benefits by enhancing T cell mediated immunity against HIV, on the
converse contrasting the well documented neurotoxicity of virus
proteins, like the envelope glycoprotein 120 against microglia,
additionally it influences the immune reconstitution following
antiretroviral therapy, preventing the immune reconstitution
inflammatory syndrome ( IRIS) while preserving the integrity of HIV
specific effector T-cell responses ( 7 ).
The vast majority of infectious disease and cancer also involve
pathology induced by the inflammation, because inflammatory responses
play a central role in inducing protective immune responses, but a
profound inflammation can exacerbate the pathology, like in viral SARS.
Patients with severe COVID-19 show higher leukocyte number, but often
present lymphopenia, reduced platelet count, abnormal respiratory
findings and also a cardiovascular and haemocoagulative affection,
increased serum levels of blood C-reactive protein, erythrocyte
sedimentation rate, D-dimer, pro-inflammatory cytokines, as TNF-alpha,
IL-1 and IL-6, and chemokines, as IL-8, compared to individuals with
mild disease or healthy controls ( 8). A cytokine storm, with vascular
inflammation/endothelial damage, could also play a role in the
hypercoagulation leading to thrombotic events in lungs, in myocardium
and kidneys. An exorbitant host inflammatory response seems to correlate
not less than the amount of viral load with the worsening of symptoms;
The combination of antiviral and anti-inflammatory drugs as experienced
in clinical practice, could lead to take into consideration clofazimine,
a drug unexpensive, well tolerated, lipid soluble, bioavailable, orally
administrated, then accumulated in monocytes and macrophages in multiple
concentrations in comparison with the plasma levels, targeting the
endocytic pathway and the autophagy process, with anti-infective and
anti-inflamamtory effects ( 9, 10 ). We would suggest a trial of an
additional regimen of clofazimine, roughly at 200 mg/day, lying on a
contrast to viral pathogenic factors and a regulation of immune system
to reduce excessive and detrimental inflammatory fire.
REFERENCES
1. Karat ABA, Jeevaratnam A, Karat S et al. Double-blind controlled
clinical trial of clofazimine in reactive phases of lepromatous leprosy.
Br. Med. J. 1970; 1: 198-200.
2. Arbiser JL, Moschella SL. Clofazimine: A review of its medical uses
and mechanism of action. J. Am. Acad. Dermatol. 1995; 32: 241-47.
3. Fung-Leung WP, Edwards W, Liu Y et al. T cell subset and stimulation
strength dependent modulation of T cell activation by Kv 1.3 blockers.
PLoS One 2017; 12(1): e0170102.
4. Singh DK, Dwivedi VP, Ranganathan A et al. Blockade of the Kv 1.3 K+
channel enhances BCG vaccine efficacy by expanding central memory T
lymphocytes. J. Infect. Dis. 2016; 214(9): 1456-64.
5. Levis W, Rendini T. Clofazimine mechanisms of action in mycobacteria,
HIV and cancer. J. Infect. Dis. 2017; 215(9): 1488.
6. Baik J, Rosania GR. Macrophages sequester clofazimine in an
intracellular liquid crystal-like supramolecular organization. PLoS One
2012; 7(10): e47494.
7. Fukutomi Y, Maeda Y, Makino M. Apoptosis-inducing activity of
clofazimine in macrophages. Antimicrob. Agents Chemother. 2011; 55(9):
4000-5.
8. Yang CL, Qiu X, Zeng YK et al. Coronavirus disease 2019: a clinical
review. Eur. Rev. Med. Pharmacol. Sci. 2020; 24(8): 4585-96.
9. Yang N, Shen HM. Targeting the endocytic pathway and autophagy
process as a novel therapeutic strategy in COVID-19.
Int. J. Biol. Sci. 2020; 16(10): 1724-31.
10. Ingraham NE, Lotfi-Emran S, Thielen BK et al. Immunomodulation in
COVID-19. Lancet Respir. Med. 2020; S2213-2600, Epub ahead of print.