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Cytokine 149 (2022) 155742
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Systemic effects of IL-6 blockade in rheumatoid arthritis beyond the joints
Matthias Jarlborg
a
,
b
, Cem Gabay
a
,
*
a
Division of Rheumatology, University Hospital of Geneva, and Department of Pathology and Immunology, University of Geneva School of Medicine, Geneva, Switzerland
b
VIB-UGent Center for Inammation Research and Ghent University, Ghent, Belgium
ARTICLE INFO
Keywords:
Interleukin-6
IL-6 blockade
Rheumatoid arthritis
Systemic effects
ABSTRACT
Interleukin (IL)-6 is produced locally in response to an inammatory stimulus, and is able to induce systemic
manifestations at distance from the site of inammation. Its unique signaling mechanism, including classical and
trans-signaling pathways, leads to a major expansion in the number of cell types responding to IL-6. This
pleiotropic cytokine is a key factor in the pathogenesis of rheumatoid arthritis (RA) and is involved in many
extra-articular manifestations that accompany the disease. Thus, IL-6 blockade is associated with various bio-
logical effects beyond the joints. In this review, the systemic effects of IL-6 in RA comorbidities and the con-
sequences of its blockade will be discussed, including anemia of chronic disease, cardiovascular risks, bone and
muscle functions, and neuro-psychological manifestations.
1. Introduction
Interleukin (IL-) 6 is a pleiotropic pro-inammatory cytokine which
plays an important role in rheumatoid arthritis (RA) and its comorbid-
ities. As a chief stimulator of the production of most acute-phase pro-
teins, IL-6 is involved in acute inammation [1]. IL-6 is also a key player
in immune regulation, including the transition between acute and
chronic inammation [2]. Since the discovery of its role as a T-cell factor
for B cell differentiation [3] and its identication in 1986 [4], IL-6
targeting has considerably improved the management of numerous in-
ammatory rheumatic diseases, and in particular RA [5].
IL-6 expression is up-regulated by various transcription factors,
including NF-κB which is activated by other proinammatory cytokines
(such as IL-1β, TNF
α
and IL-17) [6], and by Toll-like receptors (TLRs)-
mediated signals [7]. In response to cellular stress signals, most leuco-
cytes and stromal cells are able to produce IL-6. The pleiotropic effects of
this cytokine can be explained by its peculiar signaling pathway,
engaging an heterodimer receptor formed by 1) its specic receptor, IL-
6R, expressed in a restricted manner and 2) the co-receptor, the glyco-
protein gp130 that is ubiquitously expressed in different cell types and
also used by other members of the IL-6 family of cytokines [8]. The
receptor IL-6R exists indeed in both transmembrane (IL-6R) and soluble
(sIL-6R) forms [9,10]. The classic signaling involves binding to
membrane-bound IL-6R. This receptor is only present in some cell types
such as hepatocytes, neutrophils, monocytes, and some lymphocytes.
The binding to IL-6R is followed by its dimerization with gp130 which,
in turn, allows signal transduction. Most importantly, the co-receptor
gp130 can also be activated by binding to soluble IL-6-sIL-6R com-
plexes (a process called trans-signalization). This signaling pathway leads
to a major extension in the number of cell types that can respond to IL-6.
Indeed, when circulating IL-6 levels exceed circulating sgp130 levels, IL-
6 can bind to sIL-6R and acts systemically like a hormone. Both classic
and trans-signaling pathways lead to signal transduction through the
Janus kinase (JAK) signal transducer and activator of transcription 3
(STAT3) pathway, as well as the mitogen-activated protein kinase
(MAPK) cascade [11,12].
IL-6 has numerous metabolic and homeostatic effects distant from
the site of inammation. The use of anti-IL-6R drugs in rheumatoid
arthritis (RA) for more than a decade [13] has led to a better under-
standing of the broad spectrum of action of this cytokine. RA is a
frequent autoimmune disease, characterized by a chronic and progres-
sive inammation of various organs, mostly the joints, and immune
dysregulation. Many cytokines, including IL-6, are involved in the
pathogenesis and maintenance of the disease [14]. Recently, the new
concept of signature cytokine hub considers IL-6 together with TNF-
α
as
critical cytokines node in RA [15]. In addition, RA is associated with an
increased risk of developing comorbid conditions in which IL-6 is also
directly involved [16]. These comorbidities include cardiovascular dis-
eases, infections, osteoporosis, depression, neoplasia, anemia (among
others), and are associated with higher morbidity and mortality [17]. In
this narrative review, we will discuss the key roles of IL-6 in most RA
comorbidities, namely anemia of chronic disease, cardiovascular risks,
* Corresponding author.
E-mail address: cem.gabay@unige.ch (C. Gabay).
Contents lists available at ScienceDirect
Cytokine
journal homepage: www.elsevier.com/locate/cytokine
https://doi.org/10.1016/j.cyto.2021.155742
Received 5 September 2021; Received in revised form 13 September 2021; Accepted 5 October 2021
Cytokine 149 (2022) 155742
2
bone and muscle dysfunctions, and neuro-psychological manifestations.
First, an overview of the effects of IL-6 in systemic inammation and in
systemic manifestations associated with RA will be exposed. The sub-
sequent consequences of its blockade beyond the joints will be then
discussed, whether benecial or detrimental.
2. IL-6 and systemic inammation
IL-6 plays a major role in systemic inammation and immunity. It is
rapidly synthesized and released by myeloid cells in response to various
danger signals and cytokines such as IL-1 and TNF-
α
. From the local site
of inammation, IL-6 is able to reach key organs through the blood-
stream and induces systemic responses. This process is referred to as the
acute-phase response [18]. With other cytokines, such as TNF-
α
, IL-1
and IFN-γ, IL-6 acts synergistically to induce inammatory systemic
responses [19]. However, IL-6, also known as hepatocyte-stimulary factor,
seems to have stronger and broader effects, especially on hepatocytes
[20].
Acute-phase response is accompanied by changes in plasma con-
centrations of multiple proteins [1], known as the acute-phase proteins,
the circulating levels of which change by at least 25% during inam-
mation. More specically, the levels of positive acute-phase proteins
increase, while plasma concentrations of negative acute-phase proteins
decrease (eg. albumin, transthyretin, bronectin) during the acute-
phase response. Hepatocytes express both IL-6R and gp130 allowing a
prompt response to IL-6 through the classical signaling pathway [21].
Positive acute-phase proteins include C-reactive protein (CRP), com-
plement factors and mannose-binding lectin, serum amyloid A (SAA),
brinogen, ferritin, and hepcidin (among others). Their increase in the
bloodstream facilitates the elimination of pathogens and damaged cells.
Commonly used as a biomarker of inammation, CRP has also biologic
effects: it participates to complement activation, and functions as a
pattern recognition molecule able to opsonize pathogens or damaged
cells [22]. In addition to promote inammation, acute-phase proteins –
such as brinogen and haptoglobin - are involved in coagulation and
healing. Mice decient for IL-6 exhibit severely impaired acute phase
protein production, and are unable to develop optimal responses to
trauma and certain types of pathogens [23]. Moreover, IL-6 and acute
phase response are also associated with changes in many physiological
and behavioral processes (such as fever, pain; hematopoietic and
metabolic perturbations; anorexia and somnolence). Fig. 1 summarizes
some of the numerous systemic effects of IL-6.
As mentioned in the introduction, IL-6 is not only involved in acute
inammation, but also prepares the transition to chronic and adaptive
responses. The rst steps of inammation are characterized by the inux
of neutrophils to the site of injury or infection. Their accumulation in-
duces the release of high amounts of IL-6 but also of sIL-6R by shedding
of its membrane-bound form [24,25]. The complex IL-6-sIL-6R-gp130 is
then able to stimulate stromal cells, mostly endothelial and smooth
muscle cells, but also synoviocytes [26]. Notably, trans-signaling pathway
of IL-6 is involved in endothelial activation and production monocyte
chemoattractant protein (MCP)-1 favoring transition from neutrophil to
monocyte recruitment [27]. In other terms, IL-6 trans-signaling promotes
secondary accumulation of monocytes to the site of inammation, which
is the hallmark of chronic inammation [2]. IL-6 is also involved in the
healing process by promoting differentiation of bone marrow-derived
monocytes towards macrophages and pro-resolving M2-like responses
[28,29]. Furthermore, IL-6 has anti-inammatory properties. Notably, it
stimulates the production of IL-1 and TNF-
α
antagonists such as IL-1Ra
and soluble p55 respectively [30].
Trans-signaling pathway has a pivotal role on lymphocytes and
adaptive immunity. IL-6 is involved in the differentiation of T helper
(Th) CD4+cells. Depending on the local microenvironment and
together with TGF-β and IL-23, IL-6 promotes Th17 polarization and
inhibits regulatory T cell (Treg) differentiation, favoring pro-
inammatory responses and mucosal immune defense [31,32]. IL-6
trans-signaling has also been shown to induce a rapid activation of
effector functions in cytotoxic CD8+T cells [33]. In addition, IL-6
Fig. 1. This gure summarizes the pleiotropic effects of IL-6 on various organs and tissues. The complexes formed by IL-6, its soluble receptor (sIL-6R) and by
glycoprotein (gp) 130 are able to induce various systemic effects distant from the initial site of inammation. Abbreviation: CRP (C-reactive protein), DAMPs
(damage-associated molecular patterns), HPA (hypothalamic–pituitary-adrenal axis), IFN-γ (interferon gamma), PAMPs (pathogen-associated molecular patterns),
Tfh (follicular helper T cells), Th17 (T-helper 17 cell), TNF-
α
(Tumor necrosis factor-alpha). This gure is made with illustrations obtained from https://smart.servier.
com/.
M. Jarlborg and C. Gabay
Cytokine 149 (2022) 155742
3
contributes to B cells differentiation and activation. In association with
IL-2 and IL-10, IL-6 induces the maturation of plasmablasts into early
plasma cells [34]. Originally described as a B cell stimulatory factor, IL-6
promotes the production of immunoglobulins in vitro [35]. In transgenic
mice, overexpression of IL-6 induces plasmocytosis with hyper-
gammaglobulinemia [36]. Together with IL-21 and IL-23 [37,38], IL-6 is
indeed necessary for the differentiation of follicular helper T cells (Tfh)
which, in turn, can activate B cells in germinal centers [39,40,41]. Some
recent data suggest that gp130/STAT3 signaling is involved in the
development of tertiary lymphoid structures [42]. These ectopic
lymphoid tissues are particularly important in the pathogenesis of
autoimmune diseases and autoantibodies production [43].
Hence, IL-6 orchestrates the immune response from its rst innate
steps to the late adaptive stages, including its resolution. Dysregulation
and persistent IL-6 production leads to a chronic inammation state as
seen in many inammatory and autoimmune diseases, as well as in
cancers. IL-6-producing cardiac myxoma illustrates the clinical conse-
quences of its overexpression with development of fever, increased
acute-phase proteins, lymph node enlargement and autoimmune fea-
tures including polyarthritis and autoantibody production [44]. High
levels of IL-6 are also observed in the rheumatoid synovium [45], in
hyperplastic lymph nodes from Castleman’s disease [46], or in multiple
myeloma [47]. These ndings led to the development of treatments
targeting IL-6. The rst clinical trials were conducted in patients with
multiple myeloma, with mitigated results [48]. Later, a humanized anti-
IL-6R antibody (tocilizumab) was successfully used to treat chronic in-
ammatory symptoms in Castleman’s disease [49]. Since the late 2000
s, IL-6R inhibitors, including tocilizumab and sarilumab have been
licensed for the management of RA refractory to conventional synthetic
disease modifying anti-rheumatic drugs (DMARDs). The use of IL-6R
inhibitors was associated with improvement of composite scores of
disease activity as well as with inhibition of structural damage [50–53].
Both tocilizumab and sarilumab were superior to adalimumab, a TNF
antagonist, in the control of inammatory manifestations when used as
monotherapy [54–57]. More recently, tocilizumab was proven efca-
cious in the treatment of other inammatory diseases, including sys-
temic juvenile idiopathic arthritis, adult onset-Still’s disease, and giant
cell arteritis [58–60]. In addition to their benecial effects in the control
of inammatory manifestations, IL-6 inhibitors are characterized by
their ability to suppress acute-phase proteins. A rapid and sustained
normalization of CRP levels is indeed observed upon IL-6R inhibition
[61,53,62]. This is associated with clinical improvement and the
reduction of many biomarkers of disease severity [63–65]. Tocilizumab
suppresses fever and CRP in RA patients undergoing surgery [66]. Thus,
by masking CRP elevation, IL-6 blockade rises major concerns regarding
interpretation of inammatory markers dependent on the acute-phase
response [67]. Besides improvements of systemic and joint inamma-
tion, IL-6 blockade is also associated with signicant benets on RA
comorbidities. In the following sections, we will discuss the role of IL-6
in RA comorbidities and the consequences of its blockade beyond the
joints.
3. Systemic benets of IL-6 blockade in rheumatoid arthritis
3.1. Hematological effects of IL-6
The changes in blood cell count accompanying inammation are
driven by cytokines, including IL-6 [68]. Anemia is the most frequent
extra-articular manifestation associated with RA. It affects 16% of newly
diagnosed RA patients in a British cohort [69] and has a lifetime prev-
alence of up to 60% according to older publications [70]. In addition to
its contribution to fatigue, anemia is an independent predictor of disease
severity and radiographic progression in RA [71]. Moreover, low he-
moglobin levels are associated with higher Health Assessment Ques-
tionnaire (HAQ) scores, indicative of physical disability [72]. Anemia of
chronic diseases (ACD, or inammatory anemia) is the main
presentation of anemia that occurs together with RA [73]. ACD is
typically normochromic, normocytic, and is due to iron sequestration.
IL-6 stimulates hepatocytes to produce proteins involved in iron meta-
bolism, mainly hepcidin [74], and ferritin [75]. Hepcidin, a hormone-
like peptide, inhibits intestinal iron absorption by binding to the ferro-
portin channel and promoting its internalization and degradation
[76,77]. Similarly, hepcidin inhibits the release of iron from reticulo-
endothelial cells. Serum hepcidin levels correlate with RA disease ac-
tivity, and are associated to RA comorbidities such as coronary
atherosclerosis and osteoporosis [78,79]. The increased ferritin levels
also participate to iron sequestration. Altogether, lower transferrin
saturation and lower serum iron concentrations result in ACD [80]. The
decrease in iron availability seems to be a general defense mechanism
against many pathogens [81]. Both anemia and increased brinogen
levels contribute to the elevation of erythrocyte sedimentation rate
(ESR) observed during inammation [82].
IL-6R inhibition counteracts the effects of IL-6 on iron metabolism
leading to greater iron availability. Tocilizumab induces a rapid and
sustained reduction of hepcidin levels in patients with Castleman disease
[83]. This has also been observed in RA, with improvement of anemia
[84]. In a cohort of RA patients treated with either tocilizumab or
iniximab (a TNF-inhibitor, TNFi), IL-6 blockade was more efcient to
reduce hepcidin levels and to improve anemia [85]. Hashimoto et al.
have demonstrated that tocilizumab is an independent factor associated
with the increase of hemoglobin levels [86]. In a post-hoc analysis of the
MONARCH study, sarilumab resulted in larger increase in hemoglobin
levels at week 12 and 24 compared to adalimumab. This effect was
associated with a larger decrease of hepcidin levels in the sarilumab
group. Correlations between hepcidin levels and disease activity
(including patient-reported outcomes) have been reported in RA, and
hepcidin appears to be a predictor of treatment efcacy of both sar-
ilumab and adalimumab at 24 weeks [65]. Thus, these studies suggest
that IL-6R inhibitors are treatments of choice for RA patients with ACD.
Thrombocytosis is involved in the promotion of hemostasis but also
in inammation, host defense and healing [87]. Inammatory throm-
bocytosis is also a direct consequence of IL-6 signaling. IL-6 stimulates
megakaryocytopoïeses through enhancement of thrombopoietin (TPO)
expression by hepatocytes [88,89]. Moreover, IL-6 has direct effects on
megakaryocytes differentiation in vitro [90]. In a mouse model, high IL-6
production resulted in thrombocytosis, and IL-6 blockade was followed
by platelet count normalization [91]. In RA, thrombocytosis correlates
with IL-6 levels and disease activity [92,93]. Of note, platelet count
decreases to a greater extent in RA patients treated with tocilizumab
compared to adalimumab [54]. In this clinical trial, low grade throm-
bocytopenia occurred also more frequently in the tocilizumab group
compared to adalimumab (9.3% vs 3.1%). However, no
thrombocytopenia-related complications (severe thrombocytopenia or
bleeding) were reported. Likewise, high platelet count together with low
hemoglobin levels seem to be good predictors for IL-6R inhibitor efcacy
[94].
Neutrophils are closely involved in IL-6 biology since they express IL-
6R and can secrete its soluble form in large amount, allowing trans-
signaling [24]. Data on the direct effects of IL-6 on neutrophils remain
however conicting. Clinical studies demonstrated that IL-6 blockade
induces a transient but signicant neutropenia [95]. Wright et al.
showed that tocilizumab does not induce an increase of neutrophil
apoptosis, neither affects neutrophil function [96]. Thus, one explana-
tion could be that IL-6R inhibitors increase neutrophil margination or
alter neutrophil trafcking [97]. Fortunately, there is no evidence for a
higher risk of serious infection secondary to tocilizumab induced-
neutropenia [98].
3.2. Effects of IL-6 on cardiovascular risks
RA is associated with excess of mortality compared to general pop-
ulation. The standardized mortality ratio (SMR) is estimated between
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Cytokine 149 (2022) 155742
4
1.27 and 2.26, depending on populations studied [99,100]. Presence of
extra-articular manifestations constitutes the strongest predictor of
mortality [99]. Despite the signicant decline in mortality in general
population, the death rate in the paired cohort of RA patients appeared
to stay relatively at [101]. A more recent study in a large Korean cohort
still conrms the excess of mortality in RA, with a SMR of 1.65 (95% CI
1.44–1.87). Cardiovascular disease (CVD) accounted for 14.2% of the
causes of death in this study [102]. It is estimate that up to 50% of
premature deaths in RA are attributable to CVD [103].
RA confers a signicantly higher risk of coronary heart disease
(CHD) and congestive heart failure compared to general population
[104–106]. RA patients have a 1.5 to 2-fold increased risk of CV events,
similar to the magnitude of risk in type 2 diabetes mellitus (DM) [107].
Recently, a large retrospective study showed a similar decline in 10-year
risk of acute myocardial infarction in both RA and non-RA populations,
indicating that the excess risk of CV events still persists [105].
Four major factors contribute to CV risk in RA. 1) The usual CV risks
factors (notably smoking, dyslipidemia, hypertension, obesity and DM)
coexist with a higher prevalence in RA [108,109]. 2) The use of some
treatments such as glucocorticoids and non-steroidal anti-inammatory
drugs, is associated with an increased CVD risk [110,111]. 3) The
presence of anti-citrullinated peptide antibodies (ACPAs) and rheuma-
toid factors (RFs) appeared to be independent risk factors for CVD and
CV mortality [112–114]. 4) Finally, elevated RA disease activity with
persistent inammation represents an independent and major risk factor
for CVD [115,116].
In this context, IL-6 plays a role on several levels. Systemic inam-
mation and the acute phase response – assessed by CRP levels and ESR –
are indeed associated with atherosclerosis. There are also clear links
between IL-6 and CVD [117,118]. A meta-analysis showed that one
standard deviation increase in IL-6 levels is associated with an adjusted
relative risk of 1.25 (1.19–1.32) of non-fatal myocardial infarction or
CHD death [119]. Using Mendelian randomization analysis, a study
showed that single nucleotide polymorphisms of IL6R gene leading to a
decrease in CRP levels were associated with a decreased odd of CHD
events in the general population [120]. Indeed, IL-6 directly inuences
endothelium homeostasis and promotes the progression of atheroma.
Elevated serum IL-6 levels were associated with higher coronary artery
calcications [121]. While favoring endothelial activation and mono-
cyte recruitment to the atheroma, IL-6 together with angiotensin II in-
uence atheroma stability [122–124].
The increased CV risk in RA is paradoxically associated with a
decrease of total cholesterol levels [125]. This phenomenon – called lipid
paradox – is probably due to the effects of IL-6 on lipid metabolism
[126]. IL-6 is involved in adipose tissue metabolism [127]. Notably,
high IL-6 levels are associated with an increased expression of lipopro-
tein(a) (Lp(a)), a known risk factor for premature atherosclerosis
[128–130]. In RA, Lp(a) concentrations are elevated, and associated
with disease activity and inammatory biomarkers [131]. Resident
macrophages and adipocytes are important sources of IL-6 in adipose
tissue of obese patients, and contribute to insulin resistance [132,133].
A recent cohort study of RA patients showed that IL-6 was independently
associated with the incidence of type 2 DM [134].
In mice, IL-6 treatment induced an increase of very-low-density li-
poprotein receptor in various tissues, and decreased circulating total
cholesterol and triglyceride levels. In the same mice, anti-IL6R antibody
reversed these lipid level changes [135]. In RA patients, low-density
lipoprotein cholesterol (LDL-C) and high-density lipoprotein choles-
terol (HDL-C) increased more with tocilizumab compared to adalimu-
mab. However, known lipid and lipid-associated CV-risk biomarkers
(including HDL-SAA, secretory phospholipase A2 IIA and Lp(a))
decreased more with tocilizumab than with adalimumab [136]. Another
study, comparing levels of biomarkers associated with CVD in RA pa-
tients whose disease was insufciently controlled by TNF inhibitors,
showed a similar effect of different biological treatments on CV risk-
associated biomarkers. However, tocilizumab was associated with a
better improvement of Lp(a) level and leptin/adiponectin ratio [137].
Regarding insulin resistance, an observational study demonstrated a
signicant reduction of glycosylated hemoglobin (HbA1c) in RA pa-
tients treated with tocilizumab and TNFi. This decrease was numerically
higher for tocilizumab compared to TNFi [138]. Sarilumab was also
associated with decreased HbA1c levels in a post hoc analysis regroup-
ing three placebo-controlled phase III studies [139].
The overall effects of IL-6 blockade on CV outcomes appear favor-
able. A meta-analysis concluded that tocilizumab had a CV safety prole
similar to that of other biological agents, despite the increase in
cholesterol levels [140]. A retrospective post-hoc study in tocilizumab-
treated RA patients showed that the risk of major cardiac events was
not related to changes of lipid levels over the rst 24 months of therapy,
but rather to the control of disease activity [141]. Long-term exposition
to tocilizumab was associated with a decreased incidence of serious
infections and serious cardiac dysfunctions [142]. The development of
acute myocardial infarction in RA patients using tocilizumab tends to be
low, even compared to patients with TNFi and abatacept [143]. Long
term safety of sarilumab showed comparable results [144].
Moreover, IL-6 blockade seems to have some benecial effects on
cardiovascular system. A pilot study showed an improvement of
vascular endothelial function (assessed by brachial artery ow-mediated
vasodilatation and carotid to femoral pulse wave velocity) in RA patients
after 3 and 6 months of tocilizumab treatment [145]. In RA patients
without cardiac symptoms, tocilizumab improved cardiac ejection
fraction assessed by cardiac magnetic resonance [146]. Apart from
rheumatologic conditions, a large cohort of patients with heart failure
showed that circulating levels of IL-6 were signicantly increased in
more than half of patients with heart failure, and were associated with
poorer outcome [147]. These data support the use of IL-6 blockade in RA
patients with CV disease, and more generally, suggest that IL-6 inhibi-
tion could offer interesting perspectives in individuals with CV disease.
3.3. Inuence of IL-6 on neuroendocrine system
Patient-reported outcomes (PROs) include symptoms related to pain,
function and global assessment of disease activity, overlapping with the
concept of health-related quality of life [148]. RA is frequently associ-
ated with symptoms such as pain, fatigue and mood disorders that all
have a signicant impact on the quality of life [149–151]. Thus, PROs
remain as relevant for disease activity assessment as traditional out-
comes based on less subjective variables [152–155].
Fatigue and sleep disturbance are very common in RA, with a
prevalence 4 to 8-times higher than in the general population [156]. The
causal factors of fatigue are multifactorial and appear to be related more
to pain and impaired function than to inammation itself [157,158].
Pain accompanying RA is also multifactorial, involving local inam-
mation and joint damage, but also peripheral and central nociception
[159,160]. Same observations can be made for depression and mood
disorders that readily accompany RA [161]. Furthermore, fatigue, pain
and mood are inuencing each other, leading to mutual amplication of
these symptoms [162,163].
Neurohormonal perturbations are partly responsible for these
symptoms in RA, and are also driven by inammatory processes. It is
now well established that IL-6 is associated with neuroendocrine effects
[164,165]. Interestingly, increased IL-6 levels have been observed in
major depression [166,167]. In animal model, IL-6 knockout mice
exhibit abnormal behaviors characterized by a resistance to stress [168].
Neural cells are indeed able to respond to IL-6 through trans-signaling
[169–171]. Cytokines, including IL-6, can activate the hypothal-
amic–pituitary-adrenal (HPA) axis, resulting in increased levels of the
stress hormone, cortisol [172,173]. However, patients with RA have
decreased circulating cortisol concentrations, despite elevated IL-6
levels [174]. This may be due to hyporesponsive adrenal glands or to
an altered HPA response to IL-6 [175]. In human and rat, there are some
evidences that IL-6 and its circadian pattern of secretion are involved in
M. Jarlborg and C. Gabay
Cytokine 149 (2022) 155742
5
sleep regulation [176]. In addition, cerebral structures such as the hy-
pothalamus, are able to produce IL-6 and increase its plasma concen-
trations in response to stress [177]. Thus, interactions between IL-6 and
neuroendocrine responses are occurring in both directions. For instance,
it has been shown that the emotional state during a noxious stimulus
inuences IL-6 levels [178]. IL-6 is also involved in nociceptive path-
ways, and seems to play a role in hyperalgesia. Neurons of the dorsal
root ganglions express gp130 and exposure to IL-6 increases their
responsiveness to painful stimuli [179]. Electrophysiological experi-
ments in rats demonstrated that IL-6 is able to induce sensitization of C-
bers to mechanical stimulation [180]. Other experiments on rats also
deciphered the role of IL-6 in central nociception through spinal cord
neurons [181]. Thus, IL-6 is involved in both central (spinal and supra-
supraspinal) and peripherical levels of nociception.
For these reasons, many studies have investigated the effects of IL-6R
inhibitors on PROs. The RADIATE randomized controlled study was
designed to investigate the effects of tocilizumab versus placebo on
PROs in RA refractory to TNFi. Tocilizumab was clearly superior to
placebo already after 2 weeks on several PROs, notably on pain
(measured with a visual analogue scale), disability (assessed with the
health assessment questionary, HAQ) and fatigue (evaluated by the
Functional Assessment of Chronic Illness Therapy, FACIT, score) [182].
The adjunction of sarilumab to methotrexate also improved PROs in
patients with inadequate response to methotrexate [183] or TNFi [184].
In the head-to-head MONARCH trial, sarilumab monotherapy was
associated with a better improvement of PROs compared to adalimumab
monotherapy [57]. The superiority of tocilizumab was also demon-
strated for the composite PROs 7-domain score, RA Impact of Disease
(RAID score) [185]. Regarding psychosocial symptoms, the randomized
OPTION trial demonstrated a signicant improvement of the mental
component summary (MCS) score in the tocilizumab group compared to
placebo [186]. The superiority of tocilizumab compared to adalimumab
on same score was also observed in the ADACTA trial [54]. A cohort
study showed improvement of scores reecting depression (Hamilton
Depression Score) and anxiety (Hamilton Anxiety Score) after tocilizu-
mab introduction [187]. An observational study conrmed that tocili-
zumab use was associated with decreased depressive symptoms in RA
patients compared to other biological agents [188]. However, a recent
study, conducted in patients with planned allogenic hematopoietic stem
cell transplantation, showed that a single dose of tocilizumab was not
able to improve depressive symptoms. On contrary, it resulted in a sig-
nicant worsening of multiple PROs [189]. This illustrates our still
partial knowledge of the effects of IL-6 on the neuroendocrine system.
Nevertheless, the vast majority of studies showed that IL-6 blockade is
associated with improvement on pain, fatigue and mood disorders that
accompany RA.
3.4. Role of IL-6 on muscle and bone homeostasis
IL-6 has also been described as a myokine that participates in the
crosstalk between skeletal muscle and bone during exercise. IL-6 is
indeed released upon muscle contraction with a marked increase in
bloodstream during physical exercise [190]. It is hypothesized that the
rapid release of IL-6 acts in a paracrine, autocrine and endocrine way to
induce the metabolic adaptations in response to exercise (such as the
induction of lipolyze/glycogenolysis and catabolism, activation of HPA
axis, and bone turnover stimulation) [191]. Although IL-6 is known to be
associated with insulin resistance, a study demonstrated that acute IL-6
treatment enhances glucose uptake by skeletal muscles [192]. On bone,
IL-6 promotes osteocalcin bioactivation which further participates to the
physiological adaptations to exercise [193]. It has been suggested that
IL-6 release during exercise promotes also anti-inammatory effects
through induction of IL-10 and IL-1Ra [194]. However, IL-6 over-
production in inammatory diseases such as RA has detrimental effects
on both bone and muscle. Interestingly, transgenic mice overexpressing
IL-6 present an amyotrophic phenotype that is reversed by IL-6R
antibody treatment [195]. It is believed that age-related skeletal muscle
wasting is in part due to the increase of plasmatic IL-6 levels during
aging [196,197].
The effects of IL-6 on bone remodeling have been better studied.
Chronic overexpression of IL-6 in transgenic mice induces important
alterations in cortical and trabecular microarchitecture, and precludes
the normal development of bone in prepubertal mice [198]. The same
group showed that mice expressing high levels of IL-6 during the post-
birth period developed growth impairment with a reduced level of
insulin-like growth factor-I [199,200]. This nding enlightens mecha-
nism of stunted growth that can be seen in systemic juvenile rheumatoid
arthritis. Human trochanteric bone reverse transcription-polymerase
chain reaction (RT-PCR) analysis showed increased expression of IL-6
and RANK mRNA in patients with femoral neck fragility-fracture
compared to healthy bone obtained from cadavers [201]. IL-6 and its
soluble receptor are able to induce the expression of receptor activator
of nuclear factor-κB ligand (RANKL) by broblast-like synoviocytes,
leading to osteoclast activation and bone resorption [26]. IL-6R trans-
signaling also appears to be involved in postmenopausal osteoporosis
[202].
Musculoskeletal manifestations of RA are not limited to the joints.
The disease commonly affects muscle and bone compartments, notably
osteoporosis and sarcopenia [203,204]. Patients with RA have a 2- fold
increased risk of osteoporotic fractures compared to a matched control-
population [205]. The origin is multifactorial, including disease dura-
tion and activity, and the use of some treatments such as glucocorticoids,
opioids and selective-serotonin reuptake-inhibitors [206,207]. Despite
marked improvement in RA management, the risk of vertebral fracture
remains high in RA [208]. Osteoporosis is indeed still frequent, with a
prevalence around 30% in a RA cohort [209]. However, analysis from
the German National Database conrmed a decrease of osteoporosis
prevalence in RA compared to the previous decade, indicating a bene-
cial effect of the use of more recent RA treatments [210]. Regarding
muscle mass, a recent meta-analysis reported a 31% prevalence of sar-
copenia in RA (i.e. 3 times higher than in the general population) [211].
In this study, disease activity was a predictive factor for sarcopenia, as
well as the use of glucocorticoids [212]. In addition, sarcopenia is also
associated to vertebral fractures in RA, having a synergistic effect with
osteoporosis [213].
To date, there is no evidence that IL-6 blockade protects against
fragility fractures. A recent cohort study did not nd any difference in
the risk of fractures between the different biologics used in RA [214].
However, in the MONARCH trial, procollagen type 1 N-terminal pro-
peptide (P1NP), a marker of bone formation, increased more in the
sarilumab group compared to adalimumab. Similarly, patients treated
with sarilumab had a greater reduction of RANKL compared to those
treated with adalimumab [65]. In a prospective study, tocilizumab was
associated with a decrease of C-terminal cross-linking telopeptide of
type I collagen (CTX), another biomarker of bone resorption, and with
increased bone mineral density after 2 years in ACPA-positive RA pa-
tients [215]. Less is known about the effect of IL-6 blockade on skeletal
muscle. The use of tocilizumab in RA is associated with weight gain
[216]. A recent study showed that this observation was partly related to
muscle gain (with a reduction of sarcopenia prevalence) [217]. Overall,
there are indirect evidences that IL-6 blockade is associated with
improved muscle and bone function in RA.
4. Systemic adverse effects of IL-6 blockade in rheumatoid
arthritis
Considering IL-6 broad spectrum of activities, IL-6 blockade is
obviously associated with a variety of adverse effects. As for other bio-
logic (bDMARDs) or conventional synthetic (cs)DMARDs, the major
safety concern of IL-6 inhibitors is the occurrence of serious infections
due to their immunosuppressive effects [218,219]. The role of IL-6 in
host defense against infections has been reviewed elsewhere [220]. In
M. Jarlborg and C. Gabay
Cytokine 149 (2022) 155742
6
addition, RA confers an increased risk of serious infections, which is
associated with higher mortality rate compared to the general popula-
tion [221,16,17]. This increased risk appears to be related to disease
activity [222]. Biological DMARDs are also associated with an increased
risk compared to csDMARDs [223].
A large US multi-database cohort showed no difference in the risk of
serious infections between RA patients treated with tocilizumab
compared to other biologics or tofacitinib, a Janus kinase inhibitor. But,
when used as a rst line therapy, tocilizumab was associated with an
increased risk for serious bacterial infections, including skin and soft
tissue infections as well as diverticulitis compared to TNFi and abatacept
[224]. A British prospective observational study also demonstrated an
increased risk of tocilizumab compared to etanercept (hazard ratio (HR)
of 1.22, with a 95% condence interval (CI) between 1.02 and 1.47)
[225]. The better safety prole of TNFi compared to tocilizumab was not
conrmed in a Japanese cohort study adjusting for covariates [226].
Sarilumab had the same safety prole as tocilizumab regardless of the
route of administration [227,228]. After a follow-up of 5 years, safety
prole of sarilumab in RA refractory to TNFi remained unchanged. The
most frequent adverse events were neutropenia with an incidence of
15.3 cases per 100 patients-years (PY) [229]. The incidence of serious
infection was 3.9 per 100 PY, comparable to other bDMARDs. In a cu-
mulative safety analysis, most frequent serious infections were pneu-
monia (with an incidence rate of 1 per 100 PY), followed by
gastroenteritis and urinary tract infection [230]. In this study, tocilizu-
mab was also associated with a slight increased risk of opportunistic
infections (0.23 per 100 PY), with no case reported in the control group.
These infections included mycobacterial (with 8 cases of Mycobacterium
Tuberculosis), and fungal (Candidiasis, Pneumocystis Jiroveci, and Cryp-
tococcus) infections.
Hepatic and gastrointestinal adverse events have been associated
with IL-6 blockade. Indeed, IL-6 pathways are involved in liver ho-
meostasis and regeneration [231,232]. Mice decient for IL-6 are more
prone to develop alcoholic and non-alcoholic fatty liver disease [233].
Thus, IL-6 inhibitors have been associated with signicant transaminase
elevations (with an estimated incidence of 1.3/100 PY), particularly
when associated to other hepatotoxic drugs [230,234]. Results from an
observational study showed that the increase of transaminase levels is
more frequent among patients treated with tocilizumab than with TNFi
[235]. However, these hepatic perturbations are reversible, and do not
appear to be associated with long-term hepatic lesions [236,237]. In
particular, no increase in malignant hepatic neoplasm was observed in
patients treated with tocilizumab compared to other biologics [238].
Some case reports and post-approval studies identied also pancreatitis
as a potential adverse effect of IL-6 blockade, possibly due to increased
levels of triglycerides [239]. More importantly, RA patients receiving
tocilizumab have a 2- fold higher risk of lower intestinal perforation
compared to those receiving a TNFi [240]. An increased risk of intestinal
perforation was conrmed with an adjusted HR of 4.5 (95% CI
2.01–9.99) [241]. One explanation could be the protective effect of IL-6
on intestinal mucosa. Indeed, experimental data have shown that IL-6
inhibits enterocytes cell death, and is involved in epithelial regenera-
tion [242,243]. The fact that IL-6 blockade precludes the interpretation
of acute phase biomarkers is also a potential factor that could delay
recognition of serious infections or diverticulitis. Table 1 summarizes
some of the main systemic side effects of IL-6 blockade. In general, real
world registries tend to show that IL-6R inhibitors induce a rapid and
long-term improvement of RA with a good safety prole
[235,244,245,142]. A recent meta-analysis including 88 randomized
controlled trials found that tocilizumab was associated with a better
Table 1
This table summarizes the effects of IL-6 on most RA comorbidities. The subsequent systemic effects associated to its blockade, whether benecial or detrimental, are
also presented. Abbreviation: ANC (absolute neutrophil count), bDMARD (Biologic Disease-modifying Antirheumatic Drug), CRP (C-reactive protein), ESR (eryth-
rocyte sedimentation rate), GI (gastro-intestinal), LDL (low-density lipoprotein), TB (Tuberculosis).
RA comorbidities IL-6 effects Consequences of IL-6 blockade Management of IL-6 blockade sides effects
Infections Key regulator cytokine of both innate and
adaptative immunity. Participates to the
defense against bacterial and fungal pathogen
[220]
Benecial: Good safety prole compared to other
bDMARD.
Long-term use is associated with a decreased
incidence of serious infections [142].
Detrimental: Suppression of fever and CRP [66,67].
Increase risk of serious bacterial infections, skin and
soft tissue infections, and diverticulitis. Rare
opportunistic infections (TB, fungi) [229,230].
Caution with CRP and ESR interpretation.
Treatment interruption during active infection
[252]. Perioperative interruption (>3 weeks
before surgery) [253]. Avoid glucocorticoid co-
medication.
TB screening prior treatment initiation. Avoid IL-6
blockade if latent TB [254].
Cardiovascular
diseases
Involved in endothelial activation and
homeostasis; acceleration of atheroma [119-
124].
Participates to lipid and glucide metabolism
[125-134].
Benecial: Good safety prole [140]. Reduction of
glycosylated hemoglobin (HbA1c) [138,139].
Improvement of endothelial and cardiac function
[146,147].
Detrimental: Increase of total cholesterol, LDL-
cholesterol and triglyceride levels
Assessment of lipid prole at therapy initiation,
and regular monitoring thereafter. Consider
posology reduction [252], or concomitant use of
statin [255].
Hematological Stimulates hepatocytes to produce proteins
involved in iron metabolism [74,75].
Stimulates thrombopoietin expression
[88,89].
Interacts with neutrophil trafcking [97].
Benecial: Reduction of hepcidin levels, leading to
improvement of anemia of chronic disease
[64,84,85].
Detrimental: Neutropenia (most often transient)
[95].
Thrombocytopenia [54].
Neutrophils and thrombocytes monitoring:
treatment interruption if ANC 0.5–1 ×10
9
/l.
Discontinuation if ANC <0.5 ×10
9
/l. Avoid
initiation in patients with ANC <2 ×10
9
/l [98]
Hepato-
gastrointestinal
Involved in liver homeostasis and regeneration
[231-234].
Protective effects on intestinal mucosa
[242,243].
Detrimental: Elevated transaminases (reversible,
and most often moderate) [235-237].
Increase risk of GI perforation [241].
Avoid concomitant use of other hepatotoxic
drugs. Regular monitoring with dose adjustment if
persistent transaminases elevation [237].
Caution in patients at risk for GI perforation (older
age, comorbidities such as diabetes and
diverticulitis, use of high dose glucocorticoids)
[240].
Fatigue, pain and
mood disorders
Activation and alteration of the
hypothalamic–pituitary-adrenal (HPA) axis
[172-177].
Central and peripherical pain control [178-
181].
Benecial: Improvement of patient reported
outcome [182-187]. Decreased depressive
symptoms in RA patients compared to other
biological agents [188].
Osteoporosis and
sarcopenia
Osteoclast activation and bone resorption
[26]. Chronic elevation of IL-6 promotes
muscle wasting [195-197].
Benecial: Improvement of biomarkers of bone
resorption [214,215]. Potential muscle gain
[216,217].
M. Jarlborg and C. Gabay
Cytokine 149 (2022) 155742
7
improvement of disease activity with same safety prole compared to
other bDMARDs and Janus kinase inhibitors in RA patients with inad-
equate response to at least one DMARD [246].
5. Conclusions
Originally named B-cell stimulatory factor-2 but also hepatocyte-
stimulary factor or interferon-β2, IL-6 is characterized by a wide spectrum
of action mediated by its two signaling pathways. Having both pro- and
anti-inammatory properties, IL-6 is a key regulator of inammation
and immunity. Its involvement in the pathogenesis of RA comorbidities
illustrates its pleiotropic effects. IL-6 is indeed associated with multiple
biological activities distant from the site of inammation. Likewise, IL-6
blockade has consequences far beyond the joints. The recent data on RA
suggest benecial effects of IL-6R inhibitors on many comorbidities.
Overall, IL-6 inhibition is associated with improvement of several sys-
temic manifestations, including anemia of chronic disease, CV events,
bone and muscle functions, and neuro-psychological manifestations as
assessed by PROs (mainly fatigue, mood disorders and pain). Impor-
tantly some of these systemic effects are not necessarily dependent on
the clinical efcacy of IL-6 inhibition on joint inammation.
Furthermore, IL-6R inhibitors and new antibodies directly targeting
IL-6 have increasing therapeutic applications beyond inammatory
rheumatic diseases [247]. For instance, sirukumab, an IL-6 neutralizing
antibody, is tested in patients with major depressive disorder in a phase
II study. Recently, a prospective study showed improvement in peri-
odontal status in patients with RA-associated periodontal disease [248].
Specic trans-signaling inhibition showed promising effect of olamkicept
in patients with active inammatory bowel disease in a phase 2 study
[249]. Finally, as IL-6R inhibition was already approved for treatment of
cytokine release syndrome [250], several retrospective studies and
randomized trials were conducted to test IL-6 inhibition in severe acute
respiratory syndrome associated to Covid-19 [251].
IL-6 biology, notably trans-signaling pathway and its systemic effects,
remains only partially elucidated yet. The therapeutic potential of IL-6
blockade goes far beyond joints, and is probably still in early stages.
Declaration of Competing Interest
The authors declare that they have no known competing nancial
interests or personal relationships that could have appeared to inuence
the work reported in this paper.
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