marine drugs

Review
The Role of Marine n-3 Polyunsaturated Fatty Acids in
Inflammatory-Based Disease: The Case of Rheumatoid Arthritis
Cinzia Parolini

Department of Pharmacological and Biomolecular Sciences, Rodolfo Paoletti, Università degli Studi di Milano,
Via Balzaretti 9, 20133 Milano, Italy; cinzia.parolini@unimi.it; Fax: +39-02-50318284

Abstract: Inflammation is a conserved process that involves the activation of immune and non-
immune cells aimed at protecting the host from bacteria, viruses, toxins and injury. However,
unresolved inflammation and the permanent release of pro-inflammatory mediators are responsi-
ble for the promotion of a condition called “low-grade systemic chronic inflammation”, which is
characterized by tissue and organ damage, metabolic changes and an increased susceptibility to
non-communicable diseases. Several studies have demonstrated that different dietary components
may influence modifiable risk factors for diverse chronic human pathologies. Marine n-3 polyunsatu-
rated fatty acids (n-3 PUFAs), mainly eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), are
well-recognized anti-inflammatory and immunomodulatory agents that are able to influence many
aspects of the inflammatory process. The aim of this article is to review the recent literature that
relates to the modulation of human disease, such as rheumatoid arthritis, by n-3 PUFAs.

Keywords: fish oil; inflammation; n-3 PUFAs; rheumatoid arthritis; specialized pro-resolving
mediators

1. Introduction
Chronic non-communicable diseases (NCDs) are still the most common global cause
of morbidity and mortality. These illnesses are characterized by the presence of elevated
levels of inflammatory markers, mainly cytokines and chemokines at the inflammatory site
Citation: Parolini, C. The Role of
and in the systemic circulation, and a huge infiltration of inflammatory cells at the site of
Marine n-3 Polyunsaturated Fatty
disease activity [1,2]. NCDs include metabolic syndrome, type 2 diabetes, hypertension,
Acids in Inflammatory-Based Disease:
cardiovascular disease (CVD), non-infectious respiratory disease, chronic kidney disease,
The Case of Rheumatoid Arthritis.
neurodegenerative and autoimmune diseases (i.e., rheumatoid arthritis), depression, osteo-
Mar. Drugs 2024, 22, 17. https://
porosis, age-related macular degeneration and various types of cancers [2,3].
doi.org/10.3390/md22010017
Inflammation is a conserved process that involves the activation of immune and non-
Academic Editor: Tiantian Zhang immune cells aimed at protecting the host from bacteria, viruses, toxins and injury, and,
Received: 30 November 2023
consequently, removing the pathogens and supporting tissue repair and recovery [4,5].
Revised: 15 December 2023
Within minutes of recognizing a harmful signal, the acute inflammatory response starts
Accepted: 26 December 2023
with an “onset phase” that involves the production of chemokines, cytokines, eicosanoids,
Published: 27 December 2023 proteases, vasoactive amines, neuropeptides and neurotransmitters by resident immune
and structural cells. Moreover, this process is characterized by the recruitment of differ-
ent cell types, such as granulocytes, from blood to the tissue inflammatory site [6]. In
physiological conditions, the inflammatory response is programmed to evolve in an active
Copyright: © 2023 by the author. “resolution phase” that is characterized by highly coordinated cellular and molecular events,
Licensee MDPI, Basel, Switzerland. including the release of anti-inflammatory cytokines and pro-resolving mediators, the loss
This article is an open access article
of receptors for pro-inflammatory stimuli and the activation of regulatory cells that weaken
distributed under the terms and
the activity of pro-inflammatory cells [7]. The effectiveness of the “resolution phase” is
conditions of the Creative Commons
conditional upon specific cellular mechanisms that are orchestrated by pro-resolving medi-
Attribution (CC BY) license (https://
ators engaged in halting the inflammatory response and initiating tissue repair and healing.
creativecommons.org/licenses/by/
Specifically, the recruitment of non-phlogistic monocytes and their differentiation into
4.0/).

Mar. Drugs 2024, 22, 17. https://doi.org/10.3390/md22010017 https://www.mdpi.com/journal/marinedrugs

Mar. Drugs 2024, 22, 17 2 of 16

macrophages able to clear the local leukocytes by apoptosis and subsequent phagocytosis
are some of the key events that determine the initiation of the “resolution phase” [8]. In ad-
dition, the apoptotic cells “inform” the phagocytosing macrophages that the inflammatory
response is ending, which triggers the macrophage mediator production to switch from a
pro-inflammatory (M1) to an anti-inflammatory and pro-resolving phenotype (M2) [9]. It
has been observed that the balance between the M1 and M2 macrophages is fundamental
for the proper resolution of inflammation [10]. Others cellular actors of the “resolution
phase” are (1) regulatory T cells (Tregs), which release anti-inflammatory cytokines, such
as interleukin 10 (IL-10) and transforming growth factor-beta (TGF-beta), and remove IL-2,
which is essential for the activation of T cells [11]; (2) innate lymphoid cells (ILCs), such
as ILC2, ILC3 and NK cells [12]; (3) myeloid-derived suppressor cells (MDSCs), which
possess immunomodulatory activities through the induction of Treg cell expansion and
the production of IL-10 and TGF-beta. Moreover, the MDSCs mediate the efferocytosis of
apoptotic neutrophils [13,14]. Meanwhile, the lipid mediator class switching promotes a
shift from the synthesis of prostaglandins (PGs) and leukotrienes (LTs) via 5-lipoxygenase
(LOX) in inflammatory exudates to the production of lipoxin A4 via 15-LOX and the fol-
lowing reprogramming of granulocytes to initiate the “resolution phase” [15]. As stated
above, during the “resolution phase”, several mediators are produced to prevent the ex-
acerbation of acute inflammatory mechanisms and eventually restore tissue homeostasis.
These anti-inflammatory and pro-resolving mediators display peculiar activities: (i) halting
or inhibiting neutrophil recruitment; (ii) promoting the influx of non-phlogistic monocytes;
(iii) inducing neutrophil apoptosis and efferocytosis by macrophages; (iv) promoting the
shift from M1 to M2 macrophage phenotypes; (v) organizing the return of non-apoptotic
cells to the blood or egress via the lymphatic vasculature; (vi) stimulating the cellular
repopulation of the tissue, aimed at adaptive homeostasis [16].
Nevertheless, unresolved inflammation and the permanent release of pro-inflammatory
mediators are responsible for the promotion of a condition called “low-grade systemic
chronic inflammation”, which is characterized by tissue and organ damage, metabolic
changes and an increased predisposition to NCDs [2,17]. In the last twenty years, the thera-
peutic approach has been focused on the possibility of positively impacting the “resolution
phase” of the inflammatory process [18].
Rheumatoid arthritis (RA) is an autoimmune disease that leads to progressive joint
damage, threatening the quality of life and increasing functional disability. The patho-
genesis of RA is unknown, but starting from the beginning of the 21st century, dramatic
improvements in understanding the basic mechanisms have been made, leading to signif-
icant changes in RA therapies [19,20]. Additionally, diverse studies have demonstrated
that different dietary components may influence modifiable risk factors for diverse chronic
human pathologies [21]. Particular attention has been drawn to fish consumption since it
lowers plasma lipid concentrations and attenuates inflammation. Indeed, fish is the main
source of omega-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) [22].
The aim of this article is to review the recent literature that relates to the modulation
of inflammatory-based disease, such as RA, by n-3 PUFAs.

2. n-3 Polyunsaturated Fatty Acids (n-3 PUFAs) and Specialized Pro-Resolving

Mediators (SPMs)
n-3 fatty acids are a family of n-3 PUFAs characterized by the presence of a final
double bond between carbons 3 and 4. The main components of this family are eicos-
apentaenoic (EPA), docosapentaenoic (DPA), and docosahexaenoic (DHA) acid. EPA and
DHA are abundant in the flesh of both lean and oily fish (with the greater amount being
for DHA) and in supplements, such as fish oils, cod liver oil and krill oil, and in some
algal oils [23]. It is widely recognized that the anti-inflammatory activity of n-3 PUFAs
involves their incorporation into cell membrane phospholipids at the expense of arachi-
donic acid (ARA). This effect causes a decrease in the amount of AA in the membranes
that inhibits ARA metabolism and expression of the cyclooxygenase (COX) gene, even-
Mar. Drugs 2024, 22, 17 3 of 16

tually decreasing the production of ARA-derived eicosanoids [24]. These processes are
triggered by inflammatory stimuli, which activate the phospholipase A2 enzyme that is
responsible for the hydrolysis of the sn-2 acyl chain of glycerol phospholipids, generat-
ing free AA or free EPA or DHA. Indeed, AA, an n-6 PUFA, is found to be esterified at
the sn-2 position of membrane phospholipids [25]. Three main enzymatic pathways are
responsible for eicosanoid production from ARA: (1) COX (COX1 and COX2); (2) 5-LOX,
12-LOX and 15-LOX; and (3) cytochrome 450 mixed-function oxidase enzymes (CYP450).
The classical eicosanoids are PGs, thromboxanes (TXs) and LTs, which are the best-known
mediators and regulators of inflammation [26]. Of note, human beings evolved on a diet
in which the ratio of n-6/n-3 PUFAs was about 1, whereas in Western diets, this ratio
is 15.9/1. This change upset the metabolic balance that was characteristic during evolu-
tion, when our genes were programmed to respond to a different type of diet [27]. n-6
PUFA metabolites are pro-inflammatory and pro-atherothrombotic molecules, which play
a key role in allergic reactions and inflammatory disorders, as well as in the metabolic
pathways regulating appetite and food intake that eventually lead to an increase in body
weight/obesity [28]. On the other hand, n-3 PUFAs (such as EPA and DHA) possess
anti-inflammatory, anti-aggregatory, vasodilation and bronchodilation effects [28]. Diverse
studies have demonstrated a higher activity of EPA compared with DHA [24]. However,
no consistent data on this regard have been produced up to now [24].
Several in vitro and in vivo studies demonstrated that n-3 PUFAs decrease the cell-
surface expression of adhesion molecules and the production of inflammatory cytokines
(such as tumor necrosis factor (TNF)-alpha, IL-1 beta and IL-6) and COX-2 metabolites [29].
These effects are mediated by the ability of n-3 PUFAs to impact the nuclear factor kappa
B (NFkB) pathway [23]. Specifically, NFkB is one of the transcription factors engaged in
the upregulation of genes encoding inflammatory proteins. The cytosolic and inactive
form of NFkB is a trimer, and its activation is promoted by inflammatory stimuli through a
signaling cascade that includes endotoxins (for example, lipopolysaccharides, LPS) that
bind to toll-like receptor (TLR) 4. This cascade starts with the phosphorylation of the
inhibitory subunit of NFkB, which then dissociates from the trimer; the remaining dimer is
able to translocate into the nucleus, where it binds to response elements and upregulates
inflammatory genes [30,31]. Currently, three alternative mechanisms have been proposed to
explain the ability of n-3 PUFAs to dampen inflammatory signaling via NFkB: (1) activation
of peroxisome proliferator-activated receptor (PPAR)-gamma, which physically interacts
with the dimeric form of NFkB, preventing its nuclear translocation; (2) interfering with raft
formation in the membrane of inflammatory cells via TLR 4 and myeloid differentiation
primary response gene 88 (MyD88); (3) binding to G-protein-coupled cell-membrane
receptor (GPR120), which triggers an anti-inflammatory cascade stimuli that is able to
inhibit NFkB activation [23].
Besides exerting these anti-inflammatory activities, n-3 PUFAs have been implicated
as substrates for the synthesis of specialized pro-resolving lipid mediators (SPMs). These
SPMs are molecules recognized as having a central role in inflammation resolution and
in the protection of the organism against the harmful consequences of uncontrolled in-
flammatory process [32]. SPMs, synthesized by the action of COX, LOX and CYP450
enzymes, include resolvins (Rvs), protectins (a.k.a. neuroprotectins, PD1/NPD1), maresins
(MaRs), and the novel cysteinyl-SPMs (cys-SPMs). In addition, in the presence of aspirin,
different epimers of SPMs are produced and are called aspirin-triggered (AT) SPMs [7].
These biosynthetic pathways may occur within a single cell type (if all the enzymes are
expressed) or in a transcellular manner, with the early steps occurring in one cell type
and the following once in a different cell that synthetizes the final biologically active lipid
mediator [33]. Specifically, SPMs play a key role in several pro-resolving mechanisms:
(1) limiting granulocyte chemotaxis and infiltration in vivo; (2) stimulating macrophage
phagocytosis and efferocytosis; (3) enhancing macrophage M2 polarization; (4) accelerating
wound healing; (5) reducing the production of pro-inflammatory cytokines (TNF-alpha and
IL-1beta) and lipid mediators (PGs and LTs); (6) promoting the Treg response and release of
 active lipid mediator [33]. Specifically, SPMs play a key role in several pro-resolving
mechanisms: (1) limiting granulocyte chemotaxis and infiltration in vivo; (2) stimulating
macrophage phagocytosis and efferocytosis; (3) enhancing macrophage M2 polarization;
Mar. Drugs 2024, 22, 17 (4) accelerating wound healing; (5) reducing the production of pro-inflammatory 4 of 16
cytokines (TNF-alpha and IL-1beta) and lipid mediators (PGs and LTs); (6) promoting the
Treg response and release of IL-10; (7) reducing platelet aggregation and inflammasome
formation [7]. Moreover,
IL-10; (7) reducing plateletstudies performed
aggregation in animal models
and inflammasome of both
formation [7].acute and chronic
Moreover, studies
inflammation have reported the therapeutic efficacy of SPMs [33]. These
performed in animal models of both acute and chronic inflammation have reported data could open the
atherapeutic
new strategy for theof
efficacy treatment of diverse
SPMs [33]. inflammatory-based
These data could open a new pathologies,
strategy forbeing, at least
the treatment
inofpart, freeinflammatory-based
diverse of the adverse effects commonlybeing,
pathologies, observed in clinical
at least in part,trials using
free of standard-of-
the adverse effects
care therapies
commonly [34]. in clinical trials using standard-of-care therapies [34].
observed
DHA
DHAisisthe theprecursor
precursorofofD-series
D-seriesRvs,
Rvs,PD1/NPD1,
PD1/NPD1,MaR1 MaR1and andcys-SPMs
cys-SPMs(Figure
(Figure1).1).

Figure1.
Figure Overview of
1. Overview of the
thepathways
pathwaysofof
thethe
endogenous
endogenoussynthesis of specialized
synthesis pro-resolving
of specialized media-
pro-resolving
tors (SPMs)
mediators from docosahexaenoic
(SPMs) acid (DHA).
from docosahexaenoic acid LOX, lipoxygenase.
(DHA). Note that not
LOX, lipoxygenase. all intermediates
Note that not all
and enzymesand
intermediates are indicated.
enzymes are indicated.

Studieshave
Studies havedemonstrated
demonstratedthat thatRvDs
RvDsare arestrong
strongimmunoresolvent
immunoresolventagents agentsthatthatact
act
mainlythrough
mainly through twotwo G-coupled
G-coupled receptors,
receptors, ALX/DRV1/GPR32
ALX/DRV1/GPR32 [35] [35]and
and DRV2/GPR18,
DRV2/GPR18,
whichbind
which bind specifically
specifically to
to RvD1
RvD1 and and RvD2,
RvD2, respectively
respectively [36].
[36]. PD1/NPD1,
PD1/NPD1,through throughitsits
receptor GPR37, exerts its anti-inflammatory functions in neural
receptor GPR37, exerts its anti-inflammatory functions in neural (NPD1) and immune (NPD1) and immune
systems(PD1).
systems (PD1).Studies
Studieshave
havedemonstrated
demonstrateditsitsability
abilitytotoprotect
protectthethehost
hostfrom
fromischemic
ischemic
stroke, retina degenerative disease and traumatic brain injury [37]. Structural
stroke, retina degenerative disease and traumatic brain injury [37]. Structural studies have studies have
identified a positional isomer of PD1, called PDX, that is able to inhibit platelet
identified a positional isomer of PD1, called PDX, that is able to inhibit platelet activation, activation,
enhanceinsulin
enhance insulinsensitivity
sensitivityand andreduce
reduceatherosclerosis,
atherosclerosis,even
eventhough
thoughaaspecific
specificreceptor
receptorstill
still
needs to be identified [38]. MaR1, a DHA-macrophage derived maresin
needs to be identified [38]. MaR1, a DHA-macrophage derived maresin that is synthetized that is synthetized
by12-LOX
by 12-LOXpathways
pathwayspromotes
promotesthe thefundamental
fundamentalpro-resolving
pro-resolvingfunctions
functionsofofmacrophages
macrophages
by interacting with a cell-surface leucin-rich repeat-containing G-protein-coupled receptor,
by interacting with a cell-surface leucin-rich repeat-containing G-protein-coupled
LGR6 [39]. Cys-SPMs are a group of pro-resolving and pro-repair mediators containing
receptor, LGR6 [39]. Cys-SPMs are a group of pro-resolving and pro-repair mediators
three series of peptide–lipid conjugated SPMs, such as the resolving conjugates in tissue
containing three series of peptide–lipid conjugated SPMs, such as the resolving conjugates
regeneration (RCTRs) [40], protectin conjugates in tissue regeneration (PCTRs) [41], and
in tissue regeneration (RCTRs) [40], protectin conjugates in tissue regeneration (PCTRs)
maresin conjugates in tissue regeneration (MCTRs) [42].
[41], and maresin conjugates in tissue regeneration (MCTRs) [42].
E-series Rvs (RvE1, RvE2, RvE3 and RvE4) are, instead, biosynthesized from EPA,
E-series Rvs (RvE1, RvE2, RvE3 and RvE4) are, instead, biosynthesized from EPA,
and RvE1 and RvE2 act by interacting with their receptors, ERV1/ChemR23 and BLT1,
and RvE1 and RvE2 act by interacting with their receptors, ERV1/ChemR23 and BLT1,
respectively (Figure 2A) [43]. RvE1 binding to ERV1/ChemR23 promotes the activation
respectively (Figure 2A) [43]. RvE1 binding to ERV1/ChemR23 promotes the activation of
of intracellular signals, such as kinase phosphorylation. Experimental studies using ago-
intracellular signals, such as kinase phosphorylation. Experimental studies using agonists
nists to the RVE1 receptor highlighted that the stimulation of the endogenous resolution
to the RVE1 receptor highlighted that the stimulation of the endogenous resolution
mechanisms may control both inflammation and cancer progression [37].
mechanisms maythe
Alongside control
above both inflammation
cited and cancer progression
and well-characterized DHA- and[37]. EPA-derived SPMs,
almost ten years ago, Dalli et al. identified analogous compounds synthetized from the
third marine n-3 PUFAs, i.e., DPA (Figure 2B), that have been assigned to the Rv, PD and
MaR families [44]. Specifically, they were designated as RvDn-3 DPA (RvD1,2,5n-3 DPA),
PDn-3 DPA (PD1,2,3n-3 DPA) and MaRn-3 DPA (MaR1,2,3n-3 DPA) (Figure 2) [44]. In
addition, a few years later, the same authors characterized the structure and function of
novel 13-series resolvins, named RvT1, RvT2, RvT3 and RvT4, specifically produced in
the circulation during the interaction between vascular endothelial cells and neutrophils
 Mar. Drugs 2024, 22, 17 5 of 16

(Figure 2B) [45]. Interestingly, the synthesis of these new immunomodulatory compounds
is stimulated by statins, particularly atorvastatin and pravastatin, via the nitrosylation
of COX-2, which enhances its enzymatic activity. A mouse model of arthritis has been
used to demonstrate that both atorvastatin and pravastatin increase the tissue and 5plasma
Mar. Drugs 2024, 22, x FOR PEER REVIEW of 16
concentrations of RvTs and are able to diminish the joint disease as well as leukocyte
trafficking and activation [46].

Overview
Figure2.2.Overview
Figure of ofthe
thepathways
pathwaysofofthe
theendogenous
endogenoussynthesis
synthesisofofspecialized
specializedpro-resolving
pro-resolving
mediators(SPMs)
mediators (SPMs)from
from(A) (A)eicosapentaenoic
eicosapentaenoic(EPA)
(EPA)and
and(B)
(B)docosapentaenoic
docosapentaenoic(DHA)
(DHA) acid.
acid. CYP450,
CYP450,
cytochrome
cytochrome450 450mixed
mixedfunction
functionoxidase
oxidaseenzymes;
enzymes;COX,
COX,cyclooxygenase;
cyclooxygenase;LOX,
LOX,lipoxygenase.
lipoxygenase.ItIt
should
shouldbebenoted
notedthat
thatnot
notallallintermediates
intermediatesand
andenzymes
enzymesare
areindicated.
indicated.

3. Rheumatoid
Alongside the Arthritis
above (RA)cited and well-characterized DHA- and EPA-derived SPMs,
RA is a systemic autoimmune
almost ten years ago, Dalli et al. identified disorderanalogous
that is characterized
compoundsbysynthetized
chronic inflammation
from the
of the
third joints,n-3
marine manifested
PUFAs, i.e., as swelling,
DPA (Figure pain,
2B),functional
that haveimpairment
been assigned andtomorning
the Rv, PD stiffness,
and
andfamilies
MaR the production of autoantibodies,
[44]. Specifically, they were i.e., rheumatoid
designated factorDPA
as RvDn-3 (a high-affinity
(RvD1,2,5n-3autoanti-
DPA),
body DPA
PDn-3 against the Fc portion
(PD1,2,3n-3 DPA)ofand immunoglobulin) and anti-citrullinated
MaRn-3 DPA (MaR1,2,3n-3 protein
DPA) (Figure 2) antibody
[44]. In
(ACPA) [47].
addition, a fewAdditionally,
years later, the RAsame
includes systemic
authors features, the
characterized suchstructure
as cardiovascular
and functiondisease
of
(CVD), and pulmonary, psychological, and skeletal disorders [48–50].
novel 13-series resolvins, named RvT1, RvT2, RvT3 and RvT4, specifically produced in the Any peripheral
joint can beduring
circulation affected,
thebut the most commonly
interaction affected endothelial
between vascular joints are within
cells the
andfeet, knees and
neutrophils
hands. Of note, other parts of the body can be a target of this
(Figure 2B) [45]. Interestingly, the synthesis of these new immunomodulatory compounds disease, such as the skin,
iseyes, lungs, heart,
stimulated nerves
by statins, and bloodatorvastatin
particularly [49,50]. The and prevalence of RAvia
pravastatin, ranges from 0.5% toof
the nitrosylation 1%
of the population
COX-2, which enhances worldwide, with the
its enzymatic predominant
activity. A mousepercentage being women
model of arthritis has been[51]. The
used
toetiological
demonstrate agent responsible
that for triggering
both atorvastatin the onset ofincrease
and pravastatin RA is unknown.
the tissue However,
and plasma it is
well recognized that RA comprises a complex interplay among
concentrations of RvTs and are able to diminish the joint disease as well as leukocyte genotype, environmental
triggers, and
trafficking andchange [48].[46].
activation Conventional and genome-wide approaches have been applied
to identify more than 100 loci associated with the RA risk and progression [52,53]. These
3.studies have helped
Rheumatoid to better
Arthritis (RA) clarify the contribution to RA pathogenesis of fundamental
genes, pathways and cell types. Additionally, they have supplied experimental evidence
RA is a systemic autoimmune disorder that is characterized by chronic inflammation
that the genetics of RA could drive drug discovery [52,53]. Specifically, the majority of these
of the joints, manifested as swelling, pain, functional impairment and morning stiffness,
loci are genes encoding (i) MHC class II molecules, primarily the HLADR locus, which
and the production of autoantibodies, i.e., rheumatoid factor (a high-affinity autoantibody
is implicated in the T-cell recognition of autoantigens [54]; (ii) co-stimulatory pathways
against the Fc portion of immunoglobulin) and anti-citrullinated protein antibody (ACPA)
(CD28, CD40, chemokines and cytokine receptors) [55], post-translational modification
[47]. Additionally,
enzymes RA includes
(i.e., peptidyl argininesystemic
deiminase, features,
type IVsuch as cardiovascular
(PADI4)), responsible for disease (CVD),
the conversion
and pulmonary, psychological, and skeletal disorders [48–50]. Any peripheral
of peptidylarginine to citrulline] [56], and intracellular regulatory pathways (i.e., PTPN22, joint can be
affected,
TNFAIP3, STAT3) [57,58], all of which are potentially able to modify the thresholdOf
but the most commonly affected joints are within the feet, knees and hands. for
note, other parts of the body can be a target of this disease, such as
immune activation or failed regulation. These observations have been confirmed by studiesthe skin, eyes, lungs,
heart, nerves and bloodinteractions.
of gene–environment [49,50]. TheIndeed,
prevalence of RA
smoking andranges
otherfrom
forms0.5% to 1% ofstress
of bronchial the
population worldwide, with the predominant percentage being women
(e.g., exposure to silica dust) are directly associated with an increase in the RA risk among [51]. The
etiological agent responsible for triggering the onset of RA is unknown. However, it is
well recognized that RA comprises a complex interplay among genotype, environmental
triggers, and change [48]. Conventional and genome-wide approaches have been applied
to identify more than 100 loci associated with the RA risk and progression [52,53]. These
studies have helped to better clarify the contribution to RA pathogenesis of fundamental
Mar. Drugs 2024, 22, 17 6 of 16

persons with susceptibility HLA-DR4 alleles [59,60], while smoking and HLA-DRB1 alleles
work together in raising one’s risk of having ACPA [61]. Additionally, environmental
stressors of pulmonary and other barrier tissues could trigger the post-translational activity
of PADI4, eventually leading to quantitative or qualitative alterations in the citrullination
of mucosal proteins [62]. Among the citrullinate self-proteins recognized through the diag-
nostic assay are alpha-enolase, keratin, fibrinogen, fibronectin, collagen and vimentin [63].
Infection diseases caused by diverse virus and bacteria species, as well as by their products,
have been correlated with the onset of RA [64]. The formation of immune complexes during
infection may indeed stimulate the synthesis of rheumatoid factors [65]. Since it has been
observed that Porphyromonas gingivalis expresses PADI4, RA seems to be associated with
periodontal disease [66]. Lastly, the gastrointestinal microbiota has been identified as a
factor influencing the development of autoimmunity, because it is involved in maintaining
immune homeostasis and acts as a marker of the host’s health status [67,68]. Perturba-
tion of this interaction can affect mucosal and systemic immunity and promote diverse
inflammatory and autoimmune diseases such as RA [69]. Many critical questions still need
an answer; primarily, why does the systemic loss of tolerance transform a pauci-cellular
synovium into chronically inflamed tissue? Nonetheless, progress in understanding the
pathogenesis of the disease has promoted the discovery of new pharmacological treatments,
leading to improved outcomes [48].
It is conceivable that infections or traumatic insults could induce the initial inflam-
matory response in the synovium, causing synovitis. Synovium is the tissue lining the
joints, and it is the place where the infiltration of neutrophils, B and T lymphocytes and
monocyte-derived macrophages and the proliferation of fibroblast-like synovial cells, called
synoviocytes, occurs [70]. Of note, a multicenter, randomized, double-blind, controlled
study demonstrated that the selective depletion of B cells through the administration of rit-
uximab, a genetically engineered chimeric anti-CD20 monoclonal antibody, to patients with
active RA, proved efficacious in ameliorating disease symptoms [71]. As the disease devel-
ops, the cells of the synovial lining proliferate, forming an invasive pannus together with
new blood vessels, which leads to the progressive destruction of cartilage and bone [72].
This condition can lead to a multifactorial syndrome named osteosarcopenia, which is
characterized by muscle wasting and an increased risk of osteoporosis [73]. Synovial B
cells are mainly localized in T-cell–B-cell aggregates, and their activation is endorsed by
the expression of factors, including a proliferation-inducing ligand (APRIL), B-lymphocyte
stimulator (BLyS) and CC and CXC chemokines [74]. Importantly, macrophages play a key
role in synovitis. Indeed, clinically effective biological agents aim to hamper macrophage
infiltration in the synovium [75]. Specifically, by looking at the pattern of pro-inflammatory
cytokine expression, the hypothesis is that the M1 macrophage phenotype is the predom-
inant one [48]. There are diverse macrophage-activating pathways primarily involving
(i) toll-like receptors (TLRs) 2/6, 3, 4 and 8; (ii) nucleotide-associated molecular patterns;
(iii) damage-associated molecular patterns, such as bacterial, viral and putative endoge-
nous ligands; (iv) cytokines; (v) cognate interactions with T cells; (vi) immune complexes;
(vii) lipoprotein particles; (viii) liver X-receptor agonists, such as oxysterols and oxidized
low-density lipoproteins (LDL); (ix) serum amyloid A-rich high-density lipoproteins (HDL);
and (x) protease-rich microenvironments through protease-activated receptor 2 [76]. High
concentrations of different cytokines and chemokines, including IL-1beta, IL-6, IL-8, IL-21,
IL-23, IL-17A, IL-17F and TNF-alpha, have been detected in the synovial fluid of patients
with RA and have been associated with the development of the disease [77]. Of note,
TNF-alpha and IL-6 play a fundamental role in RA, which was confirmed by the successful
therapeutic blockade of membrane and soluble TNF-alpha and the IL-6 receptor in patients
affected by RA [48]. Indeed, TNF-alpha triggers the expression of cytokines, chemokines
and endothelial-cell adhesion molecules; protects synovial fibroblasts; promotes angio-
genesis; suppresses regulatory T cells; and induces pain sensation [78,79]. Meanwhile,
IL-6 orchestrates the local leukocyte activation and autoantibody production together
with systemic effects that promote acute-phase responses, anemia, cognitive disfunction,
Mar. Drugs 2024, 22, 17 7 of 16

and lipid-metabolism dysregulation [80]. An additional pathogenic pathway includes the

antigen-nonspecific, T-cell-contact-mediated activation of macrophages and fibroblasts,
acting through their ligand’s interactions, i.e., CD40-CD40L, Cd200-CD200L, intracellular
adhesion molecule 1 (ICAM-1) and leukocyte-function-associated antigen 1 [81]. Moreover,
the AA-derived lipid mediators of inflammation, PGE2, LTB4, 5-hydroxyeicosatretraenic
acid and platelet-activating factor (PAF), are also found in the synovial fluid and are be-
lieved to be involved in the recruitment of leukocytes into the diseased tissue [82]. Finally,
as stated above, RA is characterized by bone erosion that occurs rapidly (affecting 80%
of patients within 1 year after diagnosis [83]) and is correlated with prolonged, increased
inflammation [84]. Synoviocytes, a.k.a. fibroblast-like synovial cells, within the synovia
lining layer are the major source of matrix metalloproteinases (MMPs), such as MMP1, 3, 9,
10 and 13, which accelerate bone erosion in the joints [85]. The secretion of these MMPs is
stimulated by the TGF-beta signaling pathway (also called the bone morphogenic protein
(BMP) pathway) through the site-specific phosphorylation of SMAD proteins [86]. Syn-
ovial cytokines, specifically macrophage colony-stimulating factor (M-CSF) and receptor
activator of NF-kB ligands (RANKL), promote osteoclast differentiation and migration of
the periosteal surface adjacent to articular cartilage [87]. Importantly, RANKL, a member
of the TNF superfamily, exerts its activity by interacting with its receptor, RANK. Osteo-
protegrin (OPG) is a soluble decoy receptor for RANKL and inhibits RANKL functions
by competing with the binding between RANK and RANKL [88]. The activation of this
osteoclast signaling pathway leads to the expression of osteoclast-specific proteins that
are necessary for demolishing mineralized tissues, including mineralized cartilage and
subchondral bone. This acidic activity of osteoclasts leads to deep resorption pits, which
are replaced by inflammatory tissue [87]. Clinical studies have confirmed the pivotal role
of these cytokines because their inhibition halts erosion in RA [89].
The clinical diagnosis of RA is based on criteria developed by the European and
American Rheumatology Association [90] and treatments are focused on disease-modifying
antirheumatic drugs (DMARDs) that target remission of the disease [90]. Several studies
have shown that starting the treatment with DMARDs at the early stages of RA is associated
with a positive change in the progression of the disease, leading to a slowdown in joint
destruction [91]. The number of therapeutic options available for the treatment of RA has in-
creased dramatically in the past 30 years [92]. Specifically, non-steroidal anti-inflammatory
drugs, glucocorticoids [93], and DMARDs of synthetic origin (i.e., methotrexate or janus
kinase (JAK)-inhibitors) or of biological origin (i.e., TNF inhibitors, costimulation modifiers,
IL-6 inhibitors and B-cell-depleting drugs) are included in the first-line protocols for RA pa-
tients [94,95]. Additionally, validated composite disease measures, standardized strategies
such as “treat to target”, and the stringent definition of remission could help to reach the
aim of clinical remission, at least in early RA [96]. Furthermore, starting from the drugs’
mechanism of action, it has been possible to focus on several biomarkers that serve as indi-
cators of organ activity, pathogenic processes or response to treatment [97]. Several types of
biomarkers have been identified and utilized for the (i) diagnosis of disease; (ii) prediction
and assessment of prognosis; (iii) prediction and assessment of response to therapy; and
(iv) prediction and assessment of drug toxicity [98]. Nevertheless, due to the heterogeneity
of RA pathophysiology, many patients do not attain clinical remission, resulting in reduced
mobility, disability, and low quality of life [99]. Additionally, lifestyle changes (i.e., smoking
cessation, dental care, weight control), assessment of vaccination status, and management
of comorbidities should be included in standard-of-care therapies [100].
Among the modifiable factors influencing the development and the progression of RA,
smoking, alcohol and unsaturated fatty acid (FA) consumption have been implicated as the
most important predictors [101]. For this reason, even if the inflammation can be controlled
by biologic agents, appropriate nutritional intervention should still be considered for these
patients. In this context, nutrition plays both direct roles in disease development, by
carrying pro- or anti-inflammatory food components, and indirect roles, through effects
on the body mass index, visceral fat accumulation and by contributing to the onset or the
 Among the modifiable factors influencing the development and the progression of
RA, smoking, alcohol and unsaturated fatty acid (FA) consumption have been implicated
as the most important predictors [101]. For this reason, even if the inflammation can be
controlled by biologic agents, appropriate nutritional intervention should still be
Mar. Drugs 2024, 22, 17
considered for these patients. In this context, nutrition plays both direct roles in disease
8 of 16
development, by carrying pro- or anti-inflammatory food components, and indirect roles,
through effects on the body mass index, visceral fat accumulation and by contributing to
the onset or the prevention of diabetes and CVD [102]. In addition, changes in lifestyle, of
prevention of diabetes and CVD [102]. In addition, changes in lifestyle, of which healthy
which healthy eating is one pillar, physical activity, management of stress and avoiding
eating is one pillar, physical activity, management of stress and avoiding risky substances
risky substances and social connections may be effective in preventing RA. The most
and social connections may be effective in preventing RA. The most popular nutritional
popular nutritional approaches include the Mediterranean diet and dietary supplements,
approaches include the Mediterranean diet and dietary supplements, especially fish oil or
especially fish oil or n-3 PUFAs [103].
n-3 PUFAs [103].
Importantly, n-3 PUFAs and their SPM lipid mediators (Figure 3), recognized as anti-
Importantly, n-3 PUFAs and their SPM lipid mediators (Figure 3), recognized as
inflammatory molecules through their ability to suppress inflammatory signaling via
anti-inflammatory molecules through their ability to suppress inflammatory signaling
NFkB
via NFkB[20],[20],
havehave
been been
widely investigated
widely in the in
investigated context of RA. of
the context TwoRA.experimental studies
Two experimental
showed that n-3 that
studies showed PUFAs,
n-3 i.e., EPAi.e.,
PUFAs, andEPA
DHA, andreduced the incidence
DHA, reduced and severity
the incidence and of arthritis
severity of
in
arthritis in two different animal models of arthritis [20,104,105]. Additionally, these results
two different animal models of arthritis [20,104,105]. Additionally, these results
highlighted
highlighted that thatEPA
EPAwaswasmoremore effective
effective thanthan
DHADHA [104,105].
[104,105]. Furthermore,
Furthermore, IernaIerna
et al. et al.
[106]
[106] demonstrated that in mice subjected to collagen-induced arthritis,
demonstrated that in mice subjected to collagen-induced arthritis, the administration of the administration
of krill
krill oil,oil,
whichwhich provides
provides marine
marine n-3 PUFAs
n-3 PUFAs partly
partly in theinform
the form of phospholipids,
of phospholipids, was more was
more efficacious
efficacious than
than fish oil,fish oil, mainly
mainly composed composed of n-3 PUFAs
of n-3 PUFAs in triacylglycerol
in triacylglycerol form, in form,
slowing in
slowing the onset of arthritis, reducing its severity, decreasing paw swelling,
the onset of arthritis, reducing its severity, decreasing paw swelling, and reducing knee- and reducing
knee-joint pathology.
joint pathology. These results
These results arewith
are in line in line withshowing
studies studies ashowing a more
more effective effective
delivery of
delivery of marine n-3 PUFAs from phospholipids than
marine n-3 PUFAs from phospholipids than from triacylglycerols [107]. from triacylglycerols [107].

Figure 3.
Figure Overview of
3. Overview of the
the pathological
pathological pathways
pathways in
in rheumatoid
rheumatoid arthritis
arthritis and
and the
the potential
potential anti-
anti-
inflammatory mechanisms
mechanismsofofaction of of
action marine n-3 n-3
marine PUFAs as well
PUFAs as as specialized
well pro-resolving
as specialized media-
pro-resolving
mediators
tors (SPMs)(SPMs) (created
(created with Biorender.com,
with Biorender.com, accessed
accessed on 22 November
on 22 November 2023). 2023).

The dietary consumption of n-3 PUFAs could play a key role in the development of
RA. An observational study by Di Giuseppe et al. found that a dietary n-3 PUFAs intake
greater than 0.21 g/day was associated with a 35% lower risk of developing RA compared
with women consuming a reduced amount [108]. Moreover, long-term consumption of
fish >1 serving/week was correlated with a 29% reduction in RA risk compared with
<1 serving/week [108]. Similar results were reported by Rosell [109] and Pedersen [110],
confirming the association between n-3 PUFA consumption and a reduction in the devel-
opment of RA. In addition, a recent systematic review and meta-analysis, which included
seven cohort and six case-control studies, demonstrated that for every 100 g/day increment
in fish intake, there was a 15% lower risk of developing RA [111].
Of note, nutrition has been shown to have an influence on disease flares, overall
management, and clinical outcomes. One of the first studies was conducted by Kremer
et al. [112]. RA patients were treated with 1.8 g of EPA for 12 weeks. At the end of the treat-
Mar. Drugs 2024, 22, 17 9 of 16

ment, patients manifested both a reduction in (1) joint stiffness in the morning and (2) the
number of tender joints. The plasma concentration of IL-1 beta was significantly reduced
(p < 0.001) in RA patients treated with 3.6 g/day of n-3 PUFAs for 12 weeks [113]. Addition-
ally, fish oil supplementation proved to ameliorate the RA disease [114]. Specifically, this
study demonstrated a reduction in the AA/EPA ratio as well as the mean LTB4 production
by 30% and 33%, respectively, together with a drop (minus 37%) in PAF production [114].
These data were later confirmed by Dawczynski [115]. Of note, this study also detected
(i) a significant decrease in the erythrocyte membranes’ AA/EPA ratio; and (ii) an immune
response inhibition through the reduction in the number of lymphocytes and monocytes
recruited [116]. Diverse studies revealed that patients taking n-3 PUFAs achieved sig-
nificant improvements in global assessment and pain and a reduction in antirheumatic
medication (about 30%) [117–119]. In addition, in the study by Geusens et al. [118], it was
observed that a high dose (2.6 g/day) proved more efficacious in reducing RA pain than
a low dose (1.3 g/day). Meta-analyses have been published to provide information con-
cerning the influence of n-3 PUFAs on the clinical manifestation in RA patients. Goldberg
et al. [120] evaluated the pain-relieving effects of EPA/DHA in RA patients. Seventeen
randomized controlled trials (RCTs) were included in the final meta-analysis. Patients
receiving different doses of n-3 PUFAs, ranging from 1.8 to 9.6 g/day, were compared with
individuals receiving different types of placebos (such as soy oil, linoleic acid capsules, air-
filled capsules, olive oil, coconut oil, corn oil, and water). Six different pain outcomes were
identified: (1) patient-assessed pain; (2) physician-assessed pain; (3) duration of morning
stiffness; (4) number of painful and/or tender joints; (5) the Ritchie articular index [121];
(6) nonselective nonsteroidal anti-inflammatory drug (NSAID) consumption. The results
of this meta-analysis suggest that n-3 PUFA supplementation reduces patient-assessed
pain (−0.26; 95% CI: −0.49 to −0.03; p = 0.03), the number of minutes of morning stiffness
(−0.43: 95% CI: −0.72 to −0.15; p = 0.003), the number of painful and/or tender joints
(−0.29; 95% CI: −0.48 to −0.10; p = 0.003), and NSAID consumption (−0.40; 95% CI: −0.72
to −0.08; p = 0.01). However, no significant effects were observed for physician-assessed
pain (−0.14; 95% CI: −0.49 to 0.22; p = 0.45) or the Ritchie articular index (0.15; 95% CI:
−0.19 to 0.49; p = 0.40) [120]. In order to maximize the therapeutic efficacy, the authors
suggested that for future trials, (i) all studies should clearly state the dose and type of
NSAIDs used, and (ii) a non-olive oil placebo should be included as a control. The reason is
based on the anti-inflammatory proprieties of olive oil, as previously demonstrated. Indeed,
its main constituent, oleic acid, may compete with AA for incorporation into phospholipids,
while minor components, such as tyrosol and beta-sitosterol, possess anti-oxidative and
anti-inflammatory effects [120,122]. In 2012, Lee et al. published a meta-analysis consid-
ering only the ten RCTs, already included in the previous study, in which RA patients
were treated with a dose of n-3 PUFAs above 2.7 g/day for a minimum duration of three
months [123]. No clinical outcome measures were improved by n-3 PUFA supplementation,
with only a trend toward an improved tender joint count, swollen joint count, morning
stiffness, and physical function recovery observed in the n-3 PUFA-treated group. The
authors highlighted that NSAID requirements were significantly different between the
n-3 PUFA and the placebo groups. However, this association was gathered from only
two case-control studies. Among the outcomes evaluated in this meta-analysis, no results
were reported concerning the impact of n-3 PUFAs on the erythrocyte sedimentation rate
(ESR) and C-reactive protein (CRP) [124]. A more recent meta-analysis was published by
Gioxari [51]. This meta-analysis included 20 RCTs with the following inclusion criteria:
written in English; conducted in humans; oral intake of n-3 PUFAs (either as a supplement
or from food source); duration of the study greater or equal to three months; maintenance
of conventional drug treatment for the entire course of the study. The outcomes evaluated
were: (i) changes in RA disease activity (through the monitoring of 16 RA markers); (ii) in-
flammation (measuring CRP, IL-1, IL-6, TNF-alpha and LTB4); (iii) risk for CVD (assessing
CVD-related risk factors, such as TG, TC, LDL and HDL). Oral treatment with n-3 PUFAs
proved efficacious in ameliorating several RA disease markers, namely early morning
Mar. Drugs 2024, 22, 17 10 of 16

stiffness, tender joint count, the pain scale, the Ritchie articular index, improving the results
from the health assessment questionnaire, grip strength, ESR, and reducing plasma levels
of LTB4 and TG. No effects were detected on TC, LDL and HDL plasma concentrations [51].
These data were also confirmed by a randomized, single-blind intervention study. RA
patients were treated with 1800 mg/day of EPA and 1200 mg/day of DHA for 90 days.
Compared with the baseline values, RA patients showed reductions in diverse RA disease
markers and CRP levels [124]. Additionally, an in vitro study found that Rvd5 suppressed
Th17 cell differentiation and CD4+ T cell proliferation, facilitated Treg differentiation, and
inhibited osteoclastogenesis [125]. Of note, a cross-sectional study demonstrated that
taking oral over-the-counter fish oil supplementation increased DHA and EPA plasma
concentrations as well as SPM precursors levels. Specifically, they detected a rise in the
concentration of both 18-hydroxy-EPA and 17-hydroxy-DHA, which have been proved
to be potent inhibitors of macrophage-mediated pro-inflammation in addition to being
substrates for SPMs [126]. Finally, two systematic reviews highlighted, on the one hand, an
inverse correlation between the highest vs. lowest category of fish consumption and RA
risk, and on the other hand, the efficacy of a dose > 2 g/day of PUFAs in improving tender
and swollen joints, morning stiffness, and a reduction on NSAID use [127]. Meanwhile,
a meta-analysis of 23 randomized placebo-controlled trials revealed only a trend toward
beneficial effects following n-3 PUFA supplementation in improving RA disease parame-
ters [128]. The strengths of this meta-analysis are: (1) relatively large number of retrieved
trials; (2) only placebo-control clinical studies and patients with defined diagnostic criteria
were included; (3) the choice of appropriate effect estimates wherever possible [128].

4. Conclusions and Perspectives

Inflammation is a physiological process within the immune response that is involved
in protecting the organism against pathogens, in the reaction to injury and in wound heal-
ing. The inflammatory response is normally a self-limiting and resolving process, thanks
to the activation of diverse negative feedback mechanisms. Indeed, in parallel with an
appropriate functioning of the inflammatory response are numerous pro-resolving lipid me-
diators, such as n-3 PUFA-derived SPMs, that are implicated in the active “resolution phase”
of the inflammation. However, excessive or uncontrolled inflammation can be harmful and
responsible for tissue damage and for the pathogenesis of several human disease. Marine-
derived n-3 PUFAs have shown potential efficacy in reducing inflammation and promoting
resolution, thus preventing or modulating several NCDs, such as rheumatoid arthritis.
Altogether the data reported in this review show that anti-inflammatory interventions, i.e.,
high fish consumption or supplements containing n-3 PUFAs, should be the standard of
care, along with pharmacotherapy, in treating patients with RA. However, all the investiga-
tors emphasize the need for longer, larger and well-designed clinical studies to reach a final
conclusion. It is important to underline that researchers may need to focus on the diversity
of lipid-derived mediator classes to better understand the therapeutic potential of n-3 PUFA
supplements. Finally, new biomarkers of the RA disease have been identified thanks to
omics approaches, which are those coming from the investigation of lipids (lipidomics),
proteins (proteomics) and metabolites (metabolomics) [129]. Specifically, clinical lipidomics,
by allowing a detailed lipidome profiling of plasma/serum/lipoproteins and immune
cells of RA patients, could trigger the identification of so-called “personalized medicine”,
together with an improvement in the early and precise diagnosis, management of disease
progression, and evaluation of new drug strategies and outcomes [130].

Funding: This research was funded by MUR Progetto di Eccellenza.

Institutional Review Board Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The author declares no conflict of interest.
Mar. Drugs 2024, 22, 17 11 of 16

References
1. World Health Organization. Available online: https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases
(accessed on 1 January 2023).
2. Furman, D.; Campisi, J.; Verdin, E.; Carrera-Bastos, P.; Targ, S.; Franceschi, C.; Ferrucci, L.; Gilroy, D.W.; Fasano, A.; Miller, G.W.;
et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 2019, 25, 1822–1832. [CrossRef] [PubMed]
3. Ferrucci, L.; Fabbri, E. Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol.
2018, 15, 505–522. [CrossRef] [PubMed]
4. Calder, P.C.; Albers, R.; Antoine, J.-M.; Blum, S.; Bourdet-Sicard, R.; Ferns, G.A.; Folkerts, G.; Friedmann, P.S.; Frost, G.S.; Guarner,
F.; et al. Inflammatory disease processes and interactions with nutrition. Br. J. Nutr. 2009, 101, S1–S45. [CrossRef] [PubMed]
5. Netea, M.G.; Balkwill, F.; Chonchol, M.F.; Cominelli, F.; Donath, M.Y.; Giamarellos-Bourboulis, E.J.; Golenbock, D.; Gresnigt, M.S.;
Heneka, M.T.; Hoffman, H.M.; et al. A guiding map for inflammation. Nat. Immunol. 2017, 18, 826–831. [CrossRef]
6. Larsen, G.L.; Henson, P.M. Mediators of inflammation. Annu. Rev. Immunol. 1993, 1, 335–359. [CrossRef]
7. Serhan, C.N. Treating inflammation and infection in the 21st century: New hints from decoding resolution mediators and
mechanisms. FASEB J. 2017, 31, 1273–1288. [CrossRef]
8. Barnig, C.; Bezema, T.; Calder, P.C.; Charloux, A.; Frossard, N.; Garssen, J.; Haworth, O.; Dilevskaya, K.; Levi-Schaffer, F.;
Lonsdorfer, E.; et al. Activation of Resolution Pathways to Prevent and Fight Chronic Inflammation: Lessons from Asthma and
Inflammatory Bowel Disease. Front. Immunol. 2019, 10, 1699. [CrossRef]
9. Dalli, J.; Serhan, C.N. Pro-Resolving Mediators in Regulating and Conferring Macrophage Function. Front. Immunol. 2017, 8, 1400.
[CrossRef]
10. Smith, T.D.; Nagalla, R.R.; Chen, E.Y.; Liu, W.F. Harnessing macrophage plasticity for tissue regeneration. Adv. Drug Deliv. Rev.
2017, 114, 193–205. [CrossRef]
11. Li, J.; Tan, J.; Martino, M.M.; Lui, K.O. Regulatory T-Cells: Potential Regulator of Tissue Repair and Regeneration. Front. Immunol.
2018, 9, 585. [CrossRef]
12. Rauber, S.; Luber, M.; Weber, S.; Maul, L.; Soare, A.; Wohlfahrt, T.; Lin, N.-Y.; Dietel, K.; Bozec, A.; Herrmann, M.; et al. Resolution
of inflammation by interleukin-9-producing type 2 innate lymphoid cells. Nat. Med. 2017, 23, 938–944. [CrossRef] [PubMed]
13. Poe, S.L.; Arora, M.; Oriss, T.B.; Yarlagadda, M.; Isse, K.; Khare, A.; Levy, D.E.; Lee, J.S.; Mallampalli, R.K.; Chanet, Y.R.; et al.
STAT1-regulated lung MDSC-like cells produce IL-10 and efferocytose apoptotic neutrophils with relevance in resolution of
bacterial pneumonia. Mucosal Immunol. 2013, 6, 189–199. [CrossRef] [PubMed]
14. Ray, A.; Chakraborty, K.; Ray, P. Immunosuppressive MDSCs induced by TLR signaling during infection and role in resolution of
inflammation. Front. Cell. Infect. Microbiol. 2013, 3, 52. [CrossRef] [PubMed]
15. Levy, B.D.; Clish, C.B.; Schmidt, B.; Gronert, K.; Serhan, C.N. Lipid mediator class switching during acute inflammation: Signals
in resolution. Nat. Immunol. 2001, 2, 612–619. [CrossRef] [PubMed]
16. Sugimoto, M.A.; Vago, J.P.; Perretti, M.; Teixeira, M.M. Mediators of the Resolution of the Inflammatory Response. Trends Immunol.
2019, 40, 212–227. [CrossRef] [PubMed]
17. Fullerton, J.N.; Gilroy, D.W. Resolution of inflammation: A new therapeutic frontier. Nat. Rev. Drug Discov. 2016, 15, 551–567.
[CrossRef] [PubMed]
18. Gilroy, D.W.; Lawrence, T.; Perretti, M.; Rossi, A.G. Inflammatory resolution: New opportunities for drug discovery. Nat. Rev.
Drug Discov. 2004, 3, 401–416. [CrossRef] [PubMed]
19. Aletaha, D.; Smolen, J.S. Diagnosis and Management of Rheumatoid Arthritis: A Review. JAMA 2018, 320, 1360–1372. [CrossRef]
20. Figus, F.A.; Piga, M.; Azzolin, I.; McConnell, R.; Iagnocco, A. Rheumatoid arthritis: Extra-articular manifestations and comorbidi-
ties. Autoimmun. Rev. 2021, 20, 102776. [CrossRef]
21. Illiano, P.; Brambilla, R.; Parolini, C. The mutual interplay of gut microbiota, diet and human disease. FEBS J. 2020, 287, 833–855.
[CrossRef]
22. Parolini, C. Effects of Fish n-3 PUFAs on Intestinal Microbiota and Immune System. Mar. Drugs 2019, 17, 374. [CrossRef]
[PubMed]
23. Calder, P.C. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim. Biophys.
Acta 2015, 4, 469–484. [CrossRef] [PubMed]
24. Parolini, C. Marine n-3 polyunsaturated fatty acids: Efficacy on inflammatory-based disorders. Life Sci. 2020, 263, 118591.
[CrossRef] [PubMed]
25. Hansen, H.S. Dietary essential fatty acids and in vivo prostaglandin production in mammals. World Rev. Nutr. Diet. 1983, 42,
102–134. [CrossRef] [PubMed]
26. Lee, J.Y.; Sohn, K.H.; Rhee, S.H.; Hwang, D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of
cyclooxygenase-2 mediated through Toll-like receptor 4. J. Biol. Chem. 2001, 276, 16683–16689. [CrossRef] [PubMed]
27. Simopoulos, A.P. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed. Pharmacother. 2002, 56, 365–379.
[CrossRef] [PubMed]
28. Mariamenatu, A.H.; Abdu, E.M. Overconsumption of Omega-6 Polyunsaturated Fatty Acids (PUFAs) versus Deficiency of
Omega-3 PUFAs in Modern-Day Diets: The Disturbing Factor for Their “Balanced Antagonistic Metabolic Functions” in the
Human Body. J. Lipids 2021, 2021, 8848161. [CrossRef] [PubMed]
Mar. Drugs 2024, 22, 17 12 of 16

29. Kumar, A.; Takada, Y.; Boriek, A.M.; Aggarwal, B.B. Nuclear factor-kappaB: Its role in health and disease. Mol. Med. 2004, 82,
434–448. [CrossRef]
30. Perkins, N.D. Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat. Rev. Mol. Cell. Biol. 2007, 8, 49–62.
[CrossRef]
31. Gabbs, M.; Leng, S.; Devassy, J.G.; Monirujjaman, M.; Aukema, H.M. Advances in Our Understanding of Oxylipins Derived from
Dietary PUFAs. Adv. Nutr. 2015, 6, 513–540. [CrossRef]
32. Spite, M.; Norling, L.V.; Summers, L.; Yang, R.; Cooper, D.; Petasis, N.A.; Flower, R.J.; Perretti, M.; Serhan, C.N. Resolvin D2 is a
potent regulator of leukocytes and controls microbial sepsis. Nature 2009, 461, 1287–1291. [CrossRef] [PubMed]
33. Panigrahy, D.; Gilligan, M.M.; Serhan, C.N.; Kashfi, K. Resolution of inflammation: An organizing principle in biology and
medicine. Pharmacol. Ther. 2021, 227, 107879. [CrossRef] [PubMed]
34. Serhan, C.N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 2014, 510, 92–101. [CrossRef] [PubMed]
35. Serhan, C.N.; Brain, S.D.; Buckley, C.D.; Gilroy, D.W.; Haslett, C.; O’Neill, L.A.J.; Perretti, M.; Rossi, A.G.; Wallace, J.L. Resolution
of inflammation: State of the art, definitions and terms. FASEB J. 2007, 21, 325–332. [CrossRef] [PubMed]
36. Zhang, L.; Qiu, C.; Yang, L.; Zhang, Z.; Zhang, Q.; Wang, B.; Wang, X. GPR18 expression on PMNs as biomarker for outcome in
patient with sepsis. Life Sci. 2019, 217, 49–56. [CrossRef] [PubMed]
37. Dyall, S.C.; Balas, L.; Bazan, N.G.; Brenna, J.T.; Chiang, N.; da Costa Souza, F.; Dalli, J.; Durand, T.; Galano, J.-M.; Lein, P.J.
Polyunsaturated fatty acids and fatty acid-derived lipid mediators: Recent advances in the understanding of their biosynthesis,
structures, and functions. Prog. Lipid Res. 2022, 86, 101165. [CrossRef] [PubMed]
38. Serhan, C.N.; Gotlinger, K.; Hong, S.; LU, Y.; SIEGELMAN, J.; BAER, T.; YANG, R.; COLGAN, S.P.; PETASIS, N.A. Anti-
inflammatory actions of neuroprotection D1/protectin D1 and its natural stereoisomers: Assignments of dihydroxy-containing
docosatrienes. J. Immunol. 2006, 176, 1848. [CrossRef] [PubMed]
39. Schwarz, B.; Sharma, L.; Robert, L.; Peng, X.; Bermejo, S.; Leighton, J.; Casanovas-Massana, A.; Minasyan, M.; Farhadian, S.;
Ko, A.I. Cutting Edge: Severe SARS-CoV-2 Infection in Humans Is Defined by a Shift in the Serum Lipidome, Resulting in
Dysregulation of Eicosanoid Immune Mediators. J. Immunol. 2021, 206, 329–334. [CrossRef]
40. de la Rosa, X.; Norris, P.C.; Chiang, N.; Rodriguez, A.R.; Spur, B.W.; Serhan, C.N. Identification and Complete Stereochemical
Assignments of the New Resolvin Conjugates in Tissue Regeneration in Human Tissues that Stimulate Proresolving Phagocyte
Functions and Tissue Regeneration. Am. J. Pathol. 2018, 188, 950–966. [CrossRef]
41. Ramon, S.; Dalli, J.; Sanger, J.M.; Winkler, J.W.; Aursnes, M.; Tungen, J.E.; Hansen, T.V.; Serhan, C.N. The Protectin PCTR1 Is
Produced by Human M2 Macrophages and Enhances Resolution of Infectio us Inflammation. Am. J. Pathol. 2016, 186, 962–973.
[CrossRef]
42. Dalli, J.; Sanger, J.M.; Rodriguez, A.R.; Chiang, N.; Spur, B.W.; Serhan, C.N. Identification and Actions of a Novel Third Maresin
Conjugate in Tissue Regeneration: MCTR3. PLoS ONE 2016, 11, e0149319. [CrossRef] [PubMed]
43. Chiang, N.; Serhan, C.N. Structural elucidation and physiologic functions of specialized pro-resolving mediators and their
receptors. Mol. Aspects Med. 2017, 58, 114–129. [CrossRef] [PubMed]
44. Dalli, J.; Colas, R.A.; Serhan, C.N. Novel n-3 immunoresolvents: Structures and actions. Sci. Rep. 2013, 3, 1940. [CrossRef]
[PubMed]
45. Dalli, J.; Chiang, N.; Serhan, C.N. Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections. Nat.
Med. 2015, 21, 1071. [CrossRef] [PubMed]
46. Walker, M.E.; Souza, P.R.; Colas, R.A.; Dalli, J. 13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and
pravastatin in inflammatory arthritis. FASEB J. 2017, 31, 3636–3648. [CrossRef] [PubMed]
47. Firestein, G.S. Evolving concept of rheumatoid arthritis. Nature 2003, 423, 356–361. [CrossRef] [PubMed]
48. McInnes, I.B.; Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 2011, 365, 2205–2219. [CrossRef]
49. Myasoedova, E.; Davis, J.M., III; Crowson, C.S.; Gabriel, S.E. Epidemiology of rheumatoid arthritis: Rheumatoid arthritis and
mortality. Curr. Rheumatol. Rep. 2010, 5, 379–385. [CrossRef]
50. Mason, J.C.; Libby, P. Cardiovascular disease in patients with chronic inflammation: Mechanisms underlying premature
cardiovascular events in rheumatologic conditions. Eur. Heart J. 2015, 36, 482–489. [CrossRef]
51. Gioxari, A.; Kaliora, A.C.; Marantidou, F.; Panagiotakos, D.P. Intake of ω-3 polyunsaturated fatty acids in patients with rheumatoid
arthritis: A systematic review and meta-analysis. Nutrition 2018, 45, 114. [CrossRef]
52. MacGregor, A.J.; Snieder, H.; Rigby, A.S.; Koskenvuo, M.; Kaprio, J.; Aho, K.; Silman, A.J. Characterizing the quantitative genetic
contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 2000, 43, 30–37. [CrossRef] [PubMed]
53. Okada, Y.; Wu, D.; Trynka, G.; Raj, T.; Terao, C.; Ikari, K.; Kochi, Y.; Ohmura, K.; Suzuki, A.; Yoshida, S.; et al. Genetics of
rheumatoid arthritis contributes to biology and drug discovery. Nature 2014, 506, 376–381. [CrossRef] [PubMed]
54. Gregersen, P.K.; Silver, J.; Winchester, R.J. The shared epitope hypothesis. An approach to understanding the molecular genetics
of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987, 30, 1205–1213. [CrossRef] [PubMed]
55. Felix, N.J.; Suri, A.; Salter-Cid, L.; Nadler, S.G.; Gujrathi, S.; Corbo, M.; Aranda, R. Targeting lymphocyte co-stimulation: From
bench to bedside. Autoimmunity 2010, 43, 514–525. [CrossRef] [PubMed]
56. De Rycke, L.; Peene, I.; Hoffman, I.E.A.; Kruithof, E.; Union, A.; Meheus, L.; Lebeer, K.; Wyns, B.; Vincent, C.; Mielants, H.;
et al. Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: Diagnostic value, associations with
radiological progression rate, and extra-articular manifestations. Ann. Rheum. Dis. 2004, 63, 1587–1593. [CrossRef] [PubMed]
Mar. Drugs 2024, 22, 17 13 of 16

57. Kallberg, H.; Padyukov, L.; Plenge, R.M.; Ronnelid, J.; Gregersen, P.K.; van der Helm-van Mil, A.H.M.; Toes, R.E.M.; Huizinga,
T.W.; Klareskog, L.; Alfredsson, L.; et al. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and
smoking in two subsets of rheumatoid arthritis. Am. J. Hum. Genet. 2007, 80, 867–875. [CrossRef] [PubMed]
58. Remmers, E.F.; Plenge, R.M.; Lee, A.T.; Graham, R.R.; Hom, G.; Behrens, T.W.; de Bakker, P.I.W.; Le, J.M.; Lee, H.-S.; Batliwalla,
F.; et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 2007, 357, 977–986.
[CrossRef] [PubMed]
59. Klareskog, L.; Stolt, P.; Lundberg, K.; Källberg, H.; Bengtsson, C.; Grunewald, J.; Rönnelid, J.; Harris, H.E.; Ulfgren, A.-K.;
Rantapää-Dahlqvist, S.; et al. A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA-DR (shared
epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006, 54, 38–46. [CrossRef]
60. Stolt, P.; Yahya, A.; Bengtsson, C.; Källberg, H.; Rönnelid, J.; Lundberg, I.; Klareskog, L.; Alfredsson, L.; EIRA Study Group. Silica
exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann.
Rheum. Dis. 2010, 69, 1072–1076. [CrossRef]
61. Källberg, H.; Ding, B.; Padyukov, L.; Bengtsson, C.; Rönnelid, J.; Klareskog, L.; Alfredsson, L.; EIRA Study Group. Smoking is
a major preventable risk factor for rheumatoid arthritis: Estimations of risks after various exposures to cigarette smoke. Ann.
Rheum. Dis. 2011, 70, 508–511. [CrossRef]
62. van der Woude, D.; Rantapää-Dahlqvist, S.; Ioan-Facsinay, A.; Onnekink, C.; Schwarte, C.M.; Verpoort, K.N.; Drijfhout, J.W.;
Huizinga, T.W.J.; Toes, R.E.M.; Pruijn, G.J.M. Epitope spreading of the anti-citrullinated protein antibody response occurs before
disease onset and is associated with the disease course of early arthritis. Ann. Rheum. Dis. 2010, 69, 1554–1561. [CrossRef]
63. Mahdi, H.; Fisher, B.A.; Källberg, H.; Plant, D.; Malmström, V.; Rönnelid, J.; Charles, P.; Ding, B.; Alfredsson, L.; Padyukov,
L.; et al. Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of
rheumatoid arthritis. Nat. Genet. 2009, 41, 1319–1324. [CrossRef] [PubMed]
64. Takei, M.; Kitamura, N.; Nagasawa, Y.; Tsuzuki, H.; Iwata, M.; Nagatsuka, Y.; Nakamura, H.; Imai, K.; Fujiwara, S. Are Viral
Infections Key Inducers of Autoimmune Diseases? Focus on Epstein-Barr Virus. Viruses 2022, 14, 1900. [CrossRef] [PubMed]
65. Kamphuis, S.; Kuis, W.; de Jager, W.; Teklenburg, G.; Massa, M.; Gordon, G.; Boerhof, M.; Rijkers, G.T.; Uiterwaal, C.S.; Otten,
H.G.; et al. Tolerogenic immune responses to novel T-cell epitopes from heat-shock protein 60 in juvenile idiopathic arthriti.
Lancet 2005, 366, 50–56. [CrossRef] [PubMed]
66. Wegner, N.; Wait, R.; Sroka, A.; Eick, S.; Nguyen, K.-A.; Lundberg, K.; Kinloch, A.; Culshaw, S.; Potempa, J.; Venables, P.J.
Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: Implications for
autoimmunity in rheumatoid arthritis. Arthritis Rheum. 2010, 62, 2662–2672. [CrossRef] [PubMed]
67. Manasson, J.; Blank, R.B.; Scher, J.U. The microbiome in rheumatology: Where are we and where should we go? Ann. Rheum. Dis.
2020, 79, 727–733. [CrossRef] [PubMed]
68. Scher, J.U.; Sczesnak, A.; Longman, R.S.; Segata, N.; Ubeda, C.; Bielski, C.; Rostron, T.; Cerundolo, V.; Pamer, E.G.; Abramson, S.B.;
et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2013, 2, e01202. [CrossRef]
[PubMed]
69. Attur, M.; Scher, J.U.; Abramson, S.B.; Attur, M. Role of Intestinal Dysbiosis and Nutrition in Rheumatoid Arthritis. Cells 2022, 11,
2436. [CrossRef]
70. Sweeney, S.E.; Firestein, G.S. Rheumatoid arthritis: Regulation of synovial inflammation. Int. J. Biochem. Biol. 2004, 36, 372–378.
[CrossRef]
71. Edwards, J.C.W.; Szczepanski, L.; Szechinski, J.; Filipowicz-Sosnowska, A.; Emery, P.; Close, D.R.; Stevens, R.M.; Shaw, T. Efficacy
of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 2004, 350, 2572–2581. [CrossRef]
72. Komatsu, N.; Takayanagi, H. Mechanisms of joint destruction in rheumatoid arthritis—Immune cell-fibroblast-bone interactions.
Nat. Rev. Rheumatol. 2022, 18, 415–429. [CrossRef] [PubMed]
73. Bonanni, R.; Grillo, S.G.; Cariati, I.; Tranquillo, L.; Iundusi, R.; Gasbarra, E.; Tancredi, V.; Tarantino, U. Osteosarcopenia and Pain:
Do We Have a Way Out? Biomedicines 2023, 11, 1285. [CrossRef] [PubMed]
74. Ohata, J.; Zvaifler, N.J.; Nishio, M.; Boyle, D.L.; Kalled, S.L.; Carson, D.A.; Kipps, T.J. Fibroblast-like synoviocytes of mesenchymal
origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines. J. Immunol. 2005,
174, 864–870. [CrossRef] [PubMed]
75. Haringman, J.J.; Gerlag, D.H.; Zwinderman, A.H.; Smeets, T.J.M.; Kraan, M.C.; Baeten, D.; McInnes, I.B.; Bresnihan, B.; Tak, P.P.
Synovial tissue macrophages: A sensitive biomarker for response to treatment in patients with rheumatoid arthritis. Ann. Rheum.
Dis. 2005, 64, 834–838. [CrossRef] [PubMed]
76. Liew, F.Y.; McInnes, I.B. The role of innate mediators in inflammatory response. Mol. Immunol. 2002, 38, 887–890. [CrossRef]
[PubMed]
77. Krishnamurthy, A.; Joshua, V.; Hensvold, A.H.; Jin, T.; Sun, M.; Vivar, N.; Ytterberg, A.J.; Engström, M.; Fernandes-Cerqueira, C.;
Amara, K.; et al. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated
autoantibody-mediated bone loss. Ann. Rheum. Dis. 2016, 75, 721–729. [CrossRef] [PubMed]
78. McInnes, I.B.; Schett, G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet 2017, 389, 2328–2337. [CrossRef]
79. Hess, A.; Axmann, R.; Rech, J.; Finzel, S.; Heindl, C.; Kreitz, S.; Sergeeva, M.; Saake, M.; Garcia, M.; Kollias, G.; et al. Blockade of
TNF-α rapidly inhibits pain responses in the central nervous system. Proc. Natl. Acad. Sci. USA 2011, 108, 3731–3736. [CrossRef]
Mar. Drugs 2024, 22, 17 14 of 16

80. Li, F.; Ai, W.; Ye, J.; Wang, C.; Yuan, S.; Xie, Y.; Mo, X.; Li, W.; He, Z.; Chen, Y.; et al. Inflammatory markers and risk factors of
RA patients with depression and application of different scales in judging depression. Clin. Rheumatol. 2022, 41, 2309–2317.
[CrossRef]
81. McInnes, I.B.; Leung, B.P.; Liew, F.Y. Cell-cell interactions in synovitis. Interactions between T lymphocytes and synovial cells.
Arthritis Res. 2000, 2, 374–378. [CrossRef]
82. Marcouiller, P.; Pelletier, J.-P.; Guévremont, M.; Martel-Pelletier, J.; Ranger, P.; Laufer, S.; Reboul, P. Leukotriene and prostaglandin
synthesis pathways in osteoarthritic synovial membranes: Regulating factors for interleukin 1beta synthesis. J. Rheumatol. 2005,
32, 704–712. [PubMed]
83. van der Heijde, D.M. Joint erosions and patients with early rheumatoid arthritis. Br. J. Rheumatol. 1995, 34, 74–78. [CrossRef]
[PubMed]
84. Visser, H.; le Cessie, S.; Vos, K.; Breedveld, F.C.; Hazes, J.M.W. How to diagnose rheumatoid arthritis early: A prediction model
for persistent (erosive) arthritis. Arthritis Rheuml. 2002, 46, 357–365. [CrossRef] [PubMed]
85. Miura, Y.; Kanazawa, S. Osteochondrogenesis derived from synovial fibroblasts in inflammatory arthritis model. Inflamm. Regen.
2020, 40, 7. [CrossRef] [PubMed]
86. Müller-Ladner, U.; Ospelt, C.; Gay, S.; Distler, O.; Pap, T. Cells of the synovium in rheumatoid arthritis. Synovial fibroblasts.
Arthritis Res. Ther. 2007, 9, 223. [CrossRef] [PubMed]
87. Schett, G.; Teitelbaum, S.L. Osteoclasts and Arthritis. J. Bone Miner. Res. 2009, 24, 1142–1146. [CrossRef] [PubMed]
88. Feng, X.; Teitelbaum, S.L. Osteoclasts: New Insights. Bone Res. 2013, 1, 11–26. [CrossRef]
89. Schett, G.; Stach, C.; Zwerina, J.; Voll, R.; Manger, B. How antirheumatic drugs protect joints from damage in rheumatoid arthritis.
Arthritis Rheuml. 2008, 58, 2936–2948. [CrossRef]
90. Smolen, J.S.; Landewé, R.B.M.; Bergstra, S.A.; Kerschbaumer, A.; Sepriano, A.; Aletaha, D.; Caporali, R.; Edwards, C.J.; Hyrich,
K.L.; Pope, J.E.; et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological
disease-modifying antirheumatic drugs: 2022 update. Ann. Rheum. Dis. 2023, 82, 3–18. [CrossRef]
91. van Nies, J.A.; Krabben, A.; Huizinga, J.W.; Huizinga, T.W.J.; Kloppenburg, M.; van der Helm-van Mil, A.H.M. What is the
evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann.
Rheum. Dis. 2014, 73, 861–870. [CrossRef]
92. Burmester, G.R.; Bijlsma, J.W.J.; Cutolo, M.; McInnes, I.B. Managing rheumatic and musculoskeletal diseases—Past, present and
future. Nat. Rev. Rheumatol. 2017, 13, 443–448. [CrossRef] [PubMed]
93. Bergstra, S.A.; Sepriano, A.; Kerschbaumer, A.; van der Heijde, D.; Caporali, R.; Edwards, C.J.; Verschueren, P.; de Souza, S.;
Pope, J.E.; Takeuchi, T.; et al. Efficacy, duration of use and safety of glucocorticoids: A systematic literature review informing the
2022 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann. Rheum. Dis. 2023, 82, 81–94.
[CrossRef] [PubMed]
94. Sepriano, A.; Kerschbaumer, A.; Bergstra, S.A.; Smolen, J.S.; van der Heijde, D.; Caporali, R.; Edwards, C.J.; Verschueren, P.; de
Souza, S.; Pope, J.E.; et al. Safety of synthetic and biological DMARDs: A systematic literature review informing the 2022 update
of the EULAR recommendations for the management of rheumatoid arthritis. Ann. Rheum. Dis. 2023, 82, 107–118. [CrossRef]
[PubMed]
95. Kerschbaumer, A.; Sepriano, A.; Bergstra, S.A.; Smolen, J.S.; van der Heijde, D.; Caporali, R.; Edwards, C.J.; Verschueren, P.; de
Souza, S.; Pope, J.E.; et al. Efficacy of synthetic and biological DMARDs: A systematic literature review informing the 2022 update
of the EULAR recommendations for the management of rheumatoid arthritis. Ann. Rheum. Dis. 2023, 82, 95–106. [CrossRef]
[PubMed]
96. Smolen, J.S.; Aletaha, D.; McInnes, I.B. Rheumatoid arthritis. Lancet 2016, 388, 2023–2028. [CrossRef] [PubMed]
97. Robinson, W.H.; Mao, R. Biomarkers to guide clinical therapeutics in rheumatology? Curr. Opin. Rheumatol. 2016, 28, 168–175.
[CrossRef] [PubMed]
98. Takeuchi, T. Biomarkers as a treatment guide in rheumatoid arthritis. Clin. Immunol. 2018, 186, 59–62. [CrossRef] [PubMed]
99. Weng, H.H.; Ranganath, V.K.; Khanna, D.; Oh, M.; Furst, D.E.; Park, G.S.; Elashoff, D.A.; Sharp, J.T.; Gold, R.H.; Peter, J.B.; et al.
Equivalent responses to disease-modifying antirheumatic drugs initiated at any time during the first 15 months after symptom
onset in patients with seropositive rheumatoid arthritis. J. Rheumatol. 2010, 37, 550–557. [CrossRef]
100. Burmester, G.R.; Pope, J.E. Novel treatment strategies in rheumatoid arthritis. Lancet 2017, 389, 2338–2348. [CrossRef]
101. Tanski, W.; Swiatoniawska-Lonc, N.; Tabin, M.; Jankowska-Polanska, B. The Relationship between Fatty Acids and the Develop-
ment, Course and Treatment of Rheumatoid Arthritis. Nutrients 2022, 14, 1030. [CrossRef]
102. Scott, D.L.; Wolfe, F.; Huizinga, T.W. Rheumatoid arthritis. Lancet 2010, 9746, 1094–10108. [CrossRef] [PubMed]
103. Nikiphorou, E.; Philippou, E. Nutrition and its role in prevention and management of rheumatoid arthritis. Autoimmun. Rev.
2023, 7, 103333. [CrossRef] [PubMed]
104. Leslie, C.A.; Gonnerman, W.A.; Ullman, M.D.; Hayes, K.C.; Franzblau, C.; Cathcart, E.S. Dietary fish oil modulates macrophage
fatty acids and decreases arthritis susceptibility in mice. J. Exp. Med. 1985, 4, 1336–1349. [CrossRef] [PubMed]
105. Volker, D.H.; FitzGerald, P.E.; Garg, M.L. The eicosapentaenoic to docosahexaenoic acid ratio of diets affects the pathogenesis of
arthritis in Lew/SSN rats. J. Nutr. 2000, 3, 559–565. [CrossRef] [PubMed]
106. Ierna, M.; Kerr, A.; Scales, H.; Berge, K.; Griinari, M. Supplementation of diet with krill oil protects against experimental
rheumatoid arthritis. BMC Musculoskelet. Disord. 2010, 11, 136. [CrossRef] [PubMed]
Mar. Drugs 2024, 22, 17 15 of 16

107. Ramprasath, V.R.; Eyal, I.; Zchut, S.; Jones, P.J.H. Enhanced increase of omega-3 index in healthy individuals with response to
4-week n-3 fatty acid supplementation from krill oil versus fish oil. Lipid Health Dis. 2013, 12, 178. [CrossRef] [PubMed]
108. Di Giuseppe, D.; Vallin, A.; Bottai, M.; Askling, J.; Wolk, A. Long-term intake of dietary long-chain n-3 polyunsaturated fatty
acids and risk of rheumatoid arthritis: A prospective cohort study of women. Ann. Rheum. Dis. 2014, 11, 1949–1953. [CrossRef]
[PubMed]
109. Rosell, M.; Wesley, A.M.; Rydin, K.; Klareskog, L.; Alfredsson, L.; EIRA study group. Dietary fish and fish oil and the risk of
rheumatoid arthritis. Epidemiology 2009, 6, 896. [CrossRef]
110. Pedersen, M.; Stripp, C.; Klarlund, M.; Olsen, S.F.; Tjønneland, A.M.; Frisch, M. Diet and risk of rheumatoid arthritis in a
prospective cohort. J. Rheumatol. 2005, 7, 1249–1252.
111. Asoudeh, F.; Jayedi, A.; Kavian, Z.; Ebrahimi-Mousavi, S.; Nielsen, S.M.; Mohammadi, H. A systematic review and meta-analysis
of observational studies on the association between animal protein sources and risk of rheumatoid arthritis. Clin. Nut. 2021, 7,
4644. [CrossRef]
112. Kremer, J.M.; Bigauoette, J.; Michalek, A.V.; Timchalk, M.A.; Lininger, L.; Rynes, R.I.; Huyck, C.; Zieminski, J.; Bartholomew,
L.E. Effects of manipulation of dietary fatty acids on clinical manifestations of rheumatoid arthritis. Lancet 1985, 8422, 184–187.
[CrossRef] [PubMed]
113. Espersen, G.T.; Grunnet, N.; Lervang, H.H.; Nielsen, G.L.; Thomsen, B.S.; Faarvang, K.L.; Dyerberg, J.; Ernst, E. Decreased
interleukin-1 beta levels in plasma from rheumatoid arthritis patients after dietary supplementation with n-3 polyunsaturated
fatty acids. Clin. Rheumatol. 1992, 11, 393–395. [CrossRef] [PubMed]
114. Sperling, R.I.; Weinblatt, M.; Robin, J.L.; Ravalese, J., 3rd; Hoover, R.L.; House, F.; Coblyn, J.S.; Fraser, P.A.; Spur, B.W.; Robinson,
D.R.; et al. Effects of dietary supplementation with marine fish oil on leukocyte lipid mediator generation and function in
rheumatoid arthritis. Arthritis Rheum. 1987, 9, 988–997. [CrossRef] [PubMed]
115. Dawczynski, C.; Hackermeier, U.; Viehweger, M.; Stange, R.; Springer, M.; Jahreis, G. Incorporation of n-3 PUFA and γ-linolenic
acid in blood lipids and red blood cell lipids together with their influence on disease activity in patients with chronic inflammatory
arthritis—A randomized controlled human intervention trial. Lipids Health Dis. 2011, 10, 130. [CrossRef] [PubMed]
116. Dawczynski, C.; Schubert, R.; Hein, G.; Müller, A.; Eidner, T.; Vogelsang, H.; Basu, S.; Jahreis, G. Long-term moderate intervention
with n-3 long-chain PUFA-supplemented dairy products: Effects on pathophysiological biomarkers in patients with rheumatoid
arthritis. Br. J. Nutr. 2009, 10, 1517–1526. [CrossRef] [PubMed]
117. Belch, J.J.; Ansell, D.; Madhok, R.; O’Dowd, A.; Sturrock, R.D. Effects of altering dietary essential fatty acids on requirements
for non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis: A double blind placebo controlled study. Ann.
Rheum. Dis. 1988, 2, 96–104. [CrossRef] [PubMed]
118. Geusens, P.; Wouters, C.; Nijs, J.; Jiang, Y.; Dequeker, J. Long-term effect of omega-3 fatty acid supplementation in active
rheumatoid arthritis. A 12-month, double-blind, controlled study. Arthritis Rheum. 1994, 6, 824. [CrossRef] [PubMed]
119. Galarraga, B.; Ho, M.; Youssef, H.M.; Hill, A.; McMahon, H.; Hall, C.; Ogston, S.; Nuki, G.; Belch, J.J.F. Cod liver oil (n-3 fatty acids)
as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis. Rheumatology 2008, 5, 665–669. [CrossRef]
120. Goldberg, R.J.; Katz, J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for
inflammatory joint pain. Pain 2007, 129, 210. [CrossRef]
121. Ritchie, D.M.; Boyle, J.A.; Mclnnes, J.M.; Jasani, M.K.; Dalakos, T.G.; Grieveson, P.; Buchanan, W.W. Clinical studies with an
articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q. J. Med. 1968, 37, 393–406.
122. Moreno, J.J.; Carbonell, T.; Sanchez, T.; Miret, S.; Mitjavila, M.T. Olive oil decreases both oxidative stress and the production of
arachidonic acid metabolites by the prostaglandin G/H synthase pathway in rat macrophages. J. Nutr. 2001, 131, 2145–2149.
[CrossRef]
123. Lee, Y.-H.; Bae, S.-C.; Song, G.G. Omega-3 polyunsaturated fatty acids and the treatment of rheumatoid arthritis: A meta-analysis.
Arch. Med. Res. 2012, 43, 356–362. [CrossRef]
124. Fatel, E.C.S.; Rosa, F.T.; Alfieri, D.F.; Flauzino, T.; Scavuzzi, B.M.; Lozovoy, M.A.B.; Iriyoda, T.M.V.; Simão, A.N.C.; Dichi, I.
Beneficial effects of fish oil and cranberry juice on disease activity and inflammatory biomarkers in people with rheumatoid
arthritis. Nutrition 2021, 86, 111183. [CrossRef]
125. Yamada, H.; Saegusa, J.; Sendo, S.; Ueda, Y.; Okano, T.; Shinohara, M.; Morinobu, A. Effect of resolvin D5 on T cell differentiation
and osteoclastogenesis analyzed by lipid mediator profiling in the experimental arthritis. Sci. Rep. 2021, 11, 17312. [CrossRef]
126. Marchand, N.E.; Choi, M.Y.; Oakes, E.G.; Cook, N.R.; Stevens, E.; Gomelskaya, N.; Kotler, G.; Manson, J.E.; Lasky-Su, J.; Mora, S.;
et al. Over-the-counter fish oil supplementation and pro-resolving and pro-inflammatory lipid mediators in rheumatoid arthritis.
Prostaglandins Leukot. Essent. Fatty Acids 2023, 190, 102542. [CrossRef]
127. Sigaux, J.; Mathieu, S.; Nguyen, Y.; Sanchez, P.; Letarouilly, J.-G.; Soubrier, M.; Czernichow, S.; Flipo, R.-M.; Sellam, J.; Daïen,
C. Impact of type and dose of oral polyunsaturated fatty acid supplementation on disease activity in inflammatory rheumatic
diseases: A systematic literature review and meta-analysis. Arthritis Res. Ther. 2022, 24, 100. [CrossRef]
128. Gkiouras, K.; Grammatikopoulou, M.G.; Myrogiannis, I.; Papamitsou, T.; Rigopoulou, E.I.; Sakkas, L.I.; Bogdanos, D.P. Efficacy of
n-3 fatty acid supplementation on rheumatoid arthritis’ disease activity indicators: A systematic review and meta-analysis of
randomized placebo-controlled trials. Crit. Rev. Food Sci. Nutr. 2022, 28, 1–15. [CrossRef]
Mar. Drugs 2024, 22, 17 16 of 16

129. Puentes-Osorio, Y.; Amariles, P.; Calleja, M.A.; Merino, V.; Díaz-Coronado, J.C.; Taborda, D. Potential clinical biomarkers in
rheumatoid arthritis with an omic approach. Auto Immun. Highlights 2021, 12, 9. [CrossRef]
130. Ferreira, H.B.; Melo, T.; Paiva, A.; do Rosário Domingues, M. Insights in the Role of Lipids, Oxidative Stress and Inflammation in
Rheumatoid Arthritis Unveiled by New Trends in Lipidomic Investigations. Antioxidants 2021, 10, 45. [CrossRef]

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.