Review

Pathogenesis of rheumatoid arthritis:

one year in review 2024
A. D’Orazio1, A.L. Cirillo1, G. Greco1, E. Di Ruscio2, M. Latorre3,
F. Pisani1, A. Alunno2, I. Puxeddu1

1
Immuno-Allergology Unit, ABSTRACT Genetic and epigenetic advances
Department of Clinical and Experimental Rheumatoid arthritis (RA) is a chron- Complex interactions among genetic
Medicine, University of Pisa, Italy; ic inflammatory autoimmune disease predisposition, epigenetic regulation,
2
Department of Life, Health & Environ-
characterised by joint destruction and and environmental factors lead to the
mental Sciences, University of L’Aquila;
Internal Medicine and Nephrology extra-articular manifestations. Differ- development of RA. To date, outstand-
Division, ASL 1 Avezzano-Sulmona- ent cells and soluble components of ing progress has been made in defining
L’Aquila, San Salvatore Hospital, the innate as well as adaptive immune the mechanisms underlying RA patho-
L’Aquila, Italy; system actively contribute to the am- genesis. However, several aspects of the
3
Pulmonology Unit, Department of plification and perpetuation of the in- disease are largely unknown and they
Medical Specialties, Nuovo Ospedale flammatory processes and structural remain to be clarified. In the last year,
Apuano, Massa, Italy.
changes. To date, the knowledge on the several studies have been conducted in
Andrea D’Orazio, MD mechanisms involved in RA pathogen- order to evaluate genetic and epigenetic
Aglaia Lucia Cirillo, MD
esis is increasingly precise, mainly due modifications associated with RA, ana-
Giulia Greco, MD
Evy Di Ruscio, MD to the recent data obtained from studies lysing their link with severity degree of
Manuela Latorre, MD, PhD on genetics and molecular and cellular the disease, its clinical progression and
Francesco Pisani, MSc biology. In this review article we sum- response to therapies for further de-
Alessia Alunno, MD, PhD marised the new insights into RA patho- veloping personalised approaches that
Ilaria Puxeddu, MD, PhD genesis from original research articles can counteract these genetic modifica-
Please address correspondence to: published in the last year. tions (2-4). The most investigated and
Ilaria Puxeddu characterised genetic association in RA
U.O. Immunoallergologia Clinica, Introduction concerns the HLA antigen, particularly
Dipartimento di Medicina
Clinica e Sperimentale,
Rheumatoid arthritis (RA) is a chronic alleles in the HLA-DRB1 locus. How-
Università di Pisa, inflammatory autoimmune disease char- ever, other non-HLA loci and genes are
via Roma 67, acterised by joint destruction and extra- recognised to be involved in the devel-
56126 Pisa, Italy. articular manifestations. The mecha- opment and progression of the disease.
E-mail: ilaria.puxeddu@unipi.it nisms underlying RA pathogenesis From the analysis of the expression of
Received on August 30, 2024; accepted in involve several cellular components of quantitative trait loci (eQTL) in naive
revised form on September 5, 2024. the innate as well as adaptive immune RA patients, by using sequencing RNA
Clin Exp Rheumatol 2024; 42: 1707-1713. system, leading to the amplification and from blood samples and synovial biop-
© Copyright Clinical and perpetuation of the inflammatory pro- sies, 898 eQTL genes were identifies,
Experimental Rheumatology 2024. cesses and structural changes (1). Due 232 of which were common between
to recent advances in the research field blood and synovium compartments.
Key words: rheumatoid arthritis, of RA, some important aspects of the Particularly, a specific eQTL on HLA-
pathogenesis, environmental factors, mechanisms involved in the pathogen- DPB2 with the critical triad of single
innate immunity, adaptive immunity esis are better characterised and novel nucleotide polymorphisms (SNPs)
pathways of the disease have been iden- rs3128921, guiding synovial expres-
tified. Every single element that emerg- sion of HLA-DP2, was discovered in
es from basic and clinical research ac- the HLA region. Its gene expression
tively contributes to the identification of correlates with increased disease sever-
potential new therapeutic targets, useful ity and a higher risk of developing a
for developing a patient tailored therapy. lymphomyeloid phenotype, identifying
In this review article we summarised the potential novel therapeutic approaches
results of a Medline search of original from the time of diagnosis (5). The most
research articles in English published in recent studies conducted in the genetic
the PubMed database from January 1 to field were primarily focused on the iden-
Competing interests: none declared. December 31, 2023. tification and characterisation of new

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Rheumatoid arthritis pathogenesis / A. D’Orazio et al.

DNA polymorphisms associated with derived from RA patients, an inverse found not only in the TNF-a, but also
RA development or rapid progression association between IL-6 production in the CDKN2A promoter. Thus, exces-
of the disease, as well as their potential and miRNAs expression profile has sive hypomethylation of CDKN2A pro-
use as biomarkers. In a study conduct- been demonstrated. The IL-6 mRNA, moter was observed in the peripheral
ed in Poland, a significant association contributing to the inflammatory state blood mononuclear cells (PBMCs) pu-
emerged between the development of of the disease, exerts a negative effect rified from RA as well as from systemic
RA and nine genetic polymorphisms on the miRNAs expression profile, and lupus erythematosus (SLE) patients,
related to DNA repair genes. These ge- tocilizumab, by blocking IL-6 receptor leading to hypothesise that CDKN2A
netic polymorphisms have been identi- (IL6R), was able to counter IL-6 effects methylation levels in PBMCs could
fied as potential triggers for the develop- on the miRNAs transcription profile be used as diagnostic as well as prog-
ment of the disease, and their usefulness (10). Thus, the results of these recent nostic biomarkers in RA and in other
as biomarkers has been hypothesised. studies strongly support the usefulness autoimmune diseases (14). These find-
Their presence could indicate a genetic of certain miRNAs as biomarkers of ings introduce new perspectives in un-
predisposition, leading to increase the disease activity and allowed to identi- derstanding the molecular mechanisms
risk of developing RA in individuals fied novel targets for further pharmaco- involved in RA pathogenesis and could
belonging to this specific population logical approaches. provide relevant insights for the devel-
(6). In parallel to the discovery of ge- In addition to the innovative studies on opment of targeted therapies based on
netic variants associated with a higher the regulation of miRNAs, particular the regulation of genetic and/or epige-
risk to develop RA, special attention attention has been given to the role of netic modifications.
was given to genetic variants that can epigenetic modifications, including his-
exert protective roles. This is the case tone modifications, DNA acetylations, Take home messages
of the variants SMAD2 rs1792666 and or methylations, in the complex mecha- • Despite the HLA antigen, includ-
SMAD7 rs3736242 as well as SMAD4 nisms underlying RA pathogenesis. By ing alleles in the HLA-DRB1 locus,
rs12456284 and rs10502913, all of them analysing synovial tissues from hu- other non-HLA loci and genes are in-
belonging to a class of proteins involved man knee joints, 6 RNA modification- volved in the development and pro-
in the regulation of transforming growth related genes (ADAMDEC1, IGHM, gression of RA (2).
factor-β (TGF-β) activity, whose pres- OGN, TNFRSF11B, SCARA3, and • Genetic variants SMAD2 rs1792666,
ence has been associated to the protec- PTN) were discovered, whose methyla- SMAD7 rs3736242 and SMAD4
tive effect against the development of tion influences disease activity in RA rs12456284 and rs10502913, associ-
RA (7). Therefore, from the comparison as well as osteoarthritis patients (11). ated to high risk of developing RA,
of gene variants between RA and other Studies on DNA methylation, con- can exert protective roles in RA de-
autoimmune diseases was possible to ducted in the peripheral blood of RA velopment (7).
identify which genetic factors associ- patients and control groups, proved that • Certain miRNAs were defined in RA
ated with RA predispose to the develop- the levels of CXCR5 methylation, par- as biomarkers of disease activity and
ment of other autoimmune diseases or ticularly in the cg04537602 promoter made it possible to identify novel tar-
vice versa might exert a protective ef- region, were significantly higher in RA gets for further pharmacological ap-
fect (8). Through genetic analyses in RA patients compared to osteoarthritis and proaches (10).
patients using in parallel different bio- healthy subjects, and this also corre-
logical samples (blood, bone marrow, lated with a higher level of C-reactive New insights into
and spleen), STAT3 mutation resulted to protein (CRP), rheumatoid factor (RF) environmental factors
be much more frequent in those patients positivity and a high number of in- While the exact cause of the develop-
with T-cell large granular lymphocytic volved joints (12). Furthermore, DNA ment of RA is not fully understood, ge-
leukaemia (T-LGL) than those with methylation data allowed to improve netic susceptibility and exposure to en-
Felty’s syndrome, highlighting a possi- the identification of potential biomark- vironmental factors are known to exert
ble link between this genetic mutation ers of disease activity, but recently the an active contribution. Smoking, poor
and the development of T-LGL in RA hypomethylation of the TNF-a gene, diet, obesity, lack of physical activ-
patients (9). which plays an important role in RA, ity and psychological stress are able to
In recent years, particular relevance has been recognised to be predictor of trigger several pathways involved in the
has been given to genetic studies that disease development. TNF-a gene pro- inflammatory processes underlying RA.
focused on analysis of miRNAs as reg- moter methylation occurs differently in Up to now, an unhealthy lifestyle has
ulators of the immune response. They subjects with RA compared to healthy been recognised as one of the causes of
are non-translated RNA sequences that subjects, allowing early diagnosis in increased prevalence of cardiovascular
elicit negative control over protein ex- those patients who develop initial in- diseases (CVD) in RA patients com-
pression, and their identification and flammatory symptoms even when anti- pared to the general population (15),
characterisation has made it possible to citrullinated protein antibodies (ACPA) suggesting the potential role of lifestyle
design novel therapeutic approaches for are negative (13). We have to take in also in the development of co-morbid-
RA. For example, in the adipose tissue account that hypomethylation has been ities. In the recent years, particular at-

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 Rheumatoid arthritis pathogenesis / A. D’Orazio et al.

tention has been given to define the die- RA patients may also modify the setting carrying the SARS-CoV-2 spike pro-
tary plan for RA patients and to identify of adipokines, preventing adverse long- tein gene, was possible to demonstrate
diet intervention for reducing disease term outcomes, including fractures and a slightly increase in the incidence and
activity and to improve their quality of mortality in older adults, as well as ra- severity of RA by SARS-CoV-2 spike
life. Among the different dietary plans diographic damage progression (20). protein with parallel increased levels
actually available, the Mediterranean Besides different lifestyles, other envi- of CXCL4, anti-phospolipid antibod-
diet is primarily composed of plant- ronmental factors have been linked to ies, joint erosion and inflammation,
based foods such as fruits, vegetables, RA development. For example, the ex- supporting the direct contribution of
whole grains, seeds, legumes, olive posure to volatile organic compounds SARS-CoV-2 spike protein in acceler-
oils, and fish with associated moderate (VOC), a common environment pol- ating the development and progression
dairy intake and minimal consumption lutant, has been recently link to the de- of the disease (26). Up to now, the re-
of animal fats. Up to know it is well velopment of RA through activation of search on the role of virus infections
known that the Mediterranean diet and immune cells and amplification of their and RA development was mainly fo-
its specific components are associated activities (21). VOC are organic com- cused on the effects of single virus or
with anti-inflammatory effects, leading pounds derived from natural, anthro- its components on the development and
to improve clinical manifestations and pogenic, or mixed sources; they can be exacerbation of the disease. Therefore,
development of co-morbidities in RA inhaled or absorbed through both gas- it could be relevant to further investi-
patients. In fact, this diet plan might trointestinal system and integumentary gate the consequence of multiple virus
exert both protective and beneficial ef- system and in RA patients, but not in infections in different aspects of RA,
fects against obesity, development of the general population an increased uri- including their interaction with cellular
CVD and metabolic disorders. Several nary concentration of 7 different VOC and soluble components of the innate
studies demonstrated that in RA patient metabolites, including AMCC, CEMA, and adaptive immune system.
dietary interventions with plant-based DHBMA, 3HPMA, MHBMA3, PGA
or Mediterranean diet, together with and HMPMA has been observed (21). Take home messages
physical exercise programs, contribute How VOC contribute to the pathogen- • Mediterranean diet in RA patients
to decrease disease activity, improve esis of RA has been recently investigat- contributes to decrease the disease
metabolic status with low-moderate ed. The primary mechanism by which activity, improves metabolic status
disease activity (16), and exert benefi- VOC might exert their toxic effects is with low-moderate disease activity
cial effects on glucose metabolism (17). through induction of oxidative stress and exert beneficial effects on glu-
Moreover, weight loss in RA obese pa- that leads to redox-sensitive transcrip- cose metabolism (16, 17).
tients by dietary intervention promotes tion factors activation, including NF- • Omega-3 fatty acids and DHA echo-
enhancement in RAPID3 with increased kB. Interestingly, among the innate ing fish/seafood intake are associ-
levels of adiponectin and decreased lev- immune cells, macrophages are target ated with lower risk of developing
els of leptin, with consequent improve- cells of VOC, on which they induce RA (19).
ment in DAS28 and HAQ-DI (18). In amplification of their pro-inflammatory • The exposure to volatile organic
addition to healthy diet and regular activities. In parallel, it is recognised compounds (VOC) has been recent-
exercise, other lifestyle behaviours, in- that VOC exposure contributes to the ly linked to the development of RA
cluding not smoking, moderate alcohol onset and progression of autoimmun- through activation of immune cells
consumption and normal BMI, are as- ity by acting mainly on CD4+ T cells and amplification of their activities
sociated with a lower risk of developing among the cellular components of the (21).
RA. The underlying metabolic mecha- adaptive immune system (22).
nisms has been recently characterised In addition to pollutants exposure, vi- Novelties in the
showing that the most pronounced con- rus infections are among the major innate immune response
tribution to the positive coefficient of environmental factors recognised to It is well known that cells and cytokines
the metabolic signature came from total be triggers of RA development. Be- of the innate immune system are large-
choline, the percentage of linoleic acid/ sides Epstein-Barr virus (EBV), the ly involved in RA pathogenesis and
omega-3 fatty acid and the average di- role of SARS-CoV-2 infection in RA that their dysregulation compromises
ameter of HDL particles. Furthermore, has gained particular attention in re- synovial homeostasis, leading to the
omega-3 fatty acids and DHA echoing cent years (23-25). The interaction be- development of synovitis and erosive
fish/seafood intake are associated with tween the SARS-CoV-2 and the cellular arthritis. Research performed during
lower risk of developing the disease, components of the innate and adaptive the last year focused on neutrophils and
and these metabolic mediators are able immune systems in RA has been objec- their contribution to some mechanisms
to promote inhibition of the transcrip- tive of several studies in-vitro as well underlying RA pathogenesis. It is well
tion factors NF-kB and PPARs, all in- in-vivo. In the animal model of colla- known that neutrophils are key cells in
volved in the production of pro-inflam- gen-induced arthritis (CIA), in which the innate immune response, but their
matory cytokines (19). We have to take human fibroblasts-like synoviocytes pro-inflammatory activities and their
in account that the reduction of BMI in (FLS) were transduced with lentivirus contribution in bone destruction in RA

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Rheumatoid arthritis pathogenesis / A. D’Orazio et al.

has gained particular interest. Thus, tem. By using multi-model single-cell inflammation in the joint of RA pa-
their ability to form neutrophil extra- RNA-sequencing and surface protein tients, contributing to tissue damage
cellular traps (NETs) has been linked data coupled with histology of syno- and organ disfunction (27).
to the amplification of inflammation in vial tissues obtained from RA patients • Mast cells (MC) are required for nor-
the joint of RA patients, contributing to was possible to prove that, according mal lymphatic function and by inhib-
tissue damage and organ disfunction. to a certain state of the disease, a par- iting MC activity in TNF-transgenic
Recently, an involvement of NETs in ticular cell-type abundance phenotype mice TNF-induced inflammatory-
osteoclastogenesis through a RANKL- (CTAPs) is prevalent. For example, the erosive arthritis is amplified with de-
RANK independent way has also been presence of CTAP-M phenotype with creased lymphatic clearance (28, 29).
proposed. It seems that NETs are able to abundance of myeloid cells, M-CSF, • Multi-model single-cell RNA-se-
induce CD14+ monocytes differentia- TGF-β and fibroblasts driving myeloid quencing and surface protein data,
tion in osteoclasts and also indirectly to cells into MERTK+ HBEGF+ and coupled with histology of synovial
influence RANKL expression on T cells SPP1+ macrophages, are mainly linked tissues, make it possible to charac-
(27). By using in-vivo animal model, to wound-healing responses (30). Fur- terise specific cellular components
the role of NETs and their carbamyl- thermore, this inflammatory phenotype in different stages of RA (30).
ated protein cargo (cNETs) were deeply also includes an inflammatory CD74hi-
investigated and it was possible to dem- HLAhi fibroblasts cluster linked to low Novelties in the
onstrate that cNETs are able to promote levels of anti-citrullinated peptides an- adaptative immune response
bone destruction and alter osteoclast tibodies (anti-CCP) and low disease Among cells of the adaptive immune
biology (27). Parallel to neutrophils, it activity (30). system, regulatory T cells (Treg) play
has been recognised that other innate On the contrary, in the CTAP-EFM an active role in the immune response
immune cells such as mast cells (MC) subtype has been shown a predominant during RA pathogenesis and abnormal
actively contribute to the development expression of endothelial cells, fibro- Treg/Th17 ratio has been detected in
of the disease. MC are normally pre- blasts and macrophages, the letter with different stages of RA (1). In the CIA
sent in human synovia and these cells a less pro-inflammatory IL-1β profile, mouse model treated with natural Treg
increase in the joints of RA patients, while in CTAP-TF are mainly involved (nTreg), the knee joints showed marked
contributing to inflammation and tissue T cells and CXCL12+ SFRP1+ fibro- inflammatory changes, synovial hy-
remodelling. MC can exert pro-inflam- blasts, an inflammatory subset of fibro- perplasia, inflammatory cell infiltra-
matory activities with consequent tissue blasts which the precise function is still tion, severe pannus invasion and bone
damage, but they are also able to exert under investigation (30). Fibroblasts destruction. However, the mice treated
protective roles. This has been recently are recognised as one of the main cells with induced Treg (iTreg) showed al-
demonstrated in an in-vivo system us- involved in the regulation of RA patho- most normal synovial membrane, less
ing TNF-transgenic mice. In this animal genesis and highly expressed in human inflammatory cell infiltration and pan-
model it was possible to establish that synovia. They produce in the synovial nus invasion with no bone destruction
MC are required for normal lymphatic tissue extracellular matrix (ECM) com- (33), suggesting the beneficial regula-
function and that approaches to inhibit ponents, contribute to the recruitment tory role of iTreg in the inflammatory
MC activity exacerbates TNF-induced of T cells into the inflammatory site and processes. Furthermore, overexpres-
inflammatory-erosive arthritis with de- promote angiogenesis mainly through sion of B lymphocyte-induced matu-
creased lymphatic clearance (28). In the NOTCH expression (31). The hypoxic ration protein-1 (Blimp-1) was able
same animal model, using multi-omic and acidic environment in the synovia to promote differentiation in Treg of
spatial and single-cell transcriptomics, of RA patients is able to regulate fibro- CD4+ T cells while suppress the dif-
was possible to evaluate in the joint- blast activities, promoting cell migra- ferentiation in Th1 and Th17. Thus, this
draining lymph node sinuses during RA tion, IL-6 production and increasing limits the enhanced effect of CD4+ T
development altered cells composition glycolysis (32). Taken together, all the cells/CD4CM on cell proliferation, in-
of both innate and adaptive immune recent findings support the active role vasion, adhesion and inflammation in
system, including lymphatic endothe- of the innate immune cells, including FLS (34). As far as microRNAs (miR-
lial cells, macrophages, B and T cells. neutrophils, MC and fibroblasts in RA NAs, miR) are concerned, miR-143-3p
In particular, loss of lymphatic flow pathogenesis and contribute to better has been shown to ameliorate arthritis
through affected joint-draining lymph understand the mechanisms underlying in CIA model, polarising naive CD4+ T
nodes leads to promote tight interaction RA pathogenesis, offering novel poten- cells into Treg cells (35). Furthermore,
between effluxing macrophages and T tial therapeutic targets useful in differ- DNA hypermetilation at the Smad 7
cells via ALCAM-CD6 co-stimulation, ent stages of the disease. promoter regions may be responsible
leading to IgG2b class-switching (29). of loss of smad7 in CD4+ T cells of
We have to take in account that the in- Take home messages RA patients, which may contribute to
flammatory milieu in the synovia of RA • The ability of neutrophils to form the disease activity by enhancing Th17
patients is particularly heterogeneous in neutrophil extracellular traps (NETs) over Treg response (36). Furthermore,
terms of cells of the innate immune sys- was linked to the amplification of the possibility to treat CD4+ T follicu-

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 Rheumatoid arthritis pathogenesis / A. D’Orazio et al.

lar helper (Tfh) cells-overactive RA by availability of which exerts a power- expression profile of FA metabolism-
modulating STUB1 has been proposed. ful influence on their differentiation. related genes was significantly differ-
Targeting STUB1 and restricting the Uptake of amino acids is regulated by ent between untreated RA patients and
Tfh cells are identified as novel thera- specialised transporters, such as L- healthy controls (41), and that in CD8+
peutic strategies to control the activity type amino acid transporter 1 (LAT1), T cells from RA patients an altered FA
of the disease. also known as SLC7A5. Thus, LAT1, metabolism is present, providing novel
In the last year, important studies have strongly expressed by synovial CD4+ potential therapeutic targets to control
been performed in order to better de- T cells of patients with active RA, cor- their pro-inflammatory profile. In the
fine different T cells subtypes. Previous relates with levels of inflammatory pa- last year particular attention has been
studies demonstrated that a subset of rameters, including ESR and CRP, as given to the role of dopamine receptors
CD3+ T cells are able to co-express the well as DAS-28 scores (39). Deletion (DR) expressed on CD4+ T cells in RA.
peculiar B cell marker CD20 in various of LAT1 in murine CD4+ T cells was Different subtypes of these receptors
chronic inflammatory diseases. This proved to inhibit the development of are expressed in immune cells and they
CD20 expressing T cell subset exerts experimental arthritis and to prevent are associated with the progression or
proinflammatory activities and they are the differentiation of CD4+ T cells ex- recovery of RA in humans as well as in
depleted by anti-CD20 therapies such as pressing IFN-γ and TNF-α, without af- CIA model. For example, activation of
rituximab. The role of this specific phe- fecting Treg. Furthermore, LAT1 defi- D2-like receptors was able to mitigate
notype in RA has been better defined. cient CD4+ T cells are able to reduce symptoms of arthritis in CIA model,
CD4+ and CD8+ CD20+ T cells were transcription of genes associated with by ameliorating Th17/ Treg imbalance.
detected in the lymph nodes and joints TCR/CD28 signalling, including Akt1, Furthermore, D2R expressed on CD4+
of CIA mouse model where actively Akt2, Nfatc2, Nfkb1 and Nfkb2. Re- T cells seem to exert a protective role
produce high levels of pro-inflamma- cent functional studies revealed a sig- against the imbalance between pro- and
tory cytokines and are less susceptible nificant impairment of immune synapse anti-inflammatory T cells subsets and
to regulation by Treg cells. In addition, formation in LAT1 deficient CD4+ T the development of arthritis in the CIA
they are enriched with CXCR5+PD-1+ cells from the inflamed joints, but not model (42).
TFH and CXCR5- PD-1+ TPH cells, from the draining lymph nodes of mice Parallel to T cells, advances have been
subsets of T cells implicated in promot- with arthritis (39). Furthermore, knock- made on understanding the role of B
ing B cell response and antibody pro- out mice for the adaptor NTAL (Non- cells in RA. It is well known that B
duction within inflamed non lymphoid T cell activation linker), a molecule lymphocytes play a central role in RA
tissue (37). Thus, it has been suggested structurally and evolutionarily related pathogenesis as the precursors of au-
that this cell subset may exacerbate in- to the transmembrane adaptor LAT, toantibody secreting plasma cells, as
flammatory processes by promoting in- developed an autoimmune syndrome highly potent antigen-presenting cells,
flammatory B cells response. characterised by splenomegaly and the and as a source of various pro-inflam-
In recent years, T-cell activation Rho presence of antinuclear antibodies. Of matory cytokines. However, the effects
GTPase-activating protein (TAGAP), interest, it has been shown that NTAL of RA environment on B lymphocyte
a GTPase-activating protein specific expression is lower in activated CD4+ development remain poorly under-
for RhoA, has been found to be asso- T cells from RA patients compared to stood. There have been several studies
ciated with the pathogenesis of several healthy controls (40), supporting the investigating the role of specific classes
autoimmune diseases, including RA. potential role of this molecule in RA of B lymphocytes in RA in order to dis-
The ubiquitously expressed cytoplas- pathogenesis and in some clinical as- cover novel therapeutic targets for the
mic protein RhoA, a target factor for pects of the disease. disease. Attempts have been made to
TAGAP, is a prerequisite for the in- In the complex scenario of T cell regu- explore and classify B cell subtypes,
duction of adaptive T-cell responses. lation, we have to take in account that as in the recent study performed in the
TAGAP interference exerts its benefi- T cells are able to up-regulate glycoly- SKG mouse model of arthritis (43). In
cial effects by inhibiting the expression sis and Fatty Acid (FA) as well as cho- this model a severe reduction in pre-B
of RhoA and NLRP3, limiting the dif- lesterol synthesis in order to provide cells and immature B cells in the bone
ferentiation of Th17 cells with subse- enough energy to meet biosynthetic marrow of mice with active arthritis
quently improvement of RA symptoms. demands and clonal expansion. Then, has been observed, but no effects on
Thus, TAGAP interference is able to they return to oxidative phosphoryla- mature naïve B cells number. Like-
reduce foot swelling, bone destruction, tion and FA oxidation when the effec- wise, analysis of B cell subtypes and
synovial inflammation, and cartilage tor functions are no longer required. B cells activation in RA reveals that
erosion in CIA model, supporting the However, in chronic inflammatory seronegative patients had higher per-
beneficial effects of TAGAP interfer- diseases, including RA, T cells main- centage of transitional B cells and na-
ence on limiting RA development (38). tain a permanent activated profile that ïve B cells compared with seropositive
T cells are tightly regulated by the en- is sustained by an aberrant metabolic patients, regardless of disease activity
vironment and these cells are critically profile. Recently, it has been dem- and DMARDs therapies (44). Further-
dependent on amino acids uptake, the onstrated that the CD8+ T cell gene more, by investigating B cells response

Clinical and Experimental Rheumatology 2024 1711

Rheumatoid arthritis pathogenesis / A. D’Orazio et al.

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tion of cell-specific differential DNA methyl- patients with rheumatoid arthritis. Medicina
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• CD4+ and CD8+ CD20+ T cells are response in rheumatoid arthritis. Arthritis https://doi.org/10.3390/medicina60010038
present in the lymph nodes and joints Rheumatol 2023; 75(7): 1088-97. 16. WALRABENSTEIN W, WAGENAAR CA, van
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of CIA mouse model where exert
5. GOLDMANN K, SPILIOPOULOU A, IAKOVLI- lifestyle program for rheumatoid arthritis:
pro-inflammatory activities and are EV A et al.: Expression quantitative trait loci the ‘Plants for Joints’ randomized controlled
less susceptible to regulation by Treg analysis in rheumatoid arthritis identifies tissue trial. Rheumatology (Oxford) 2023; 62(8):
cells (37). specific variants associated with severity and 2683-91. https://
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• Specialised transporters, such as L- https://doi.org/10.1136/ard-2023-224540 17. PAPANDREOU P, GIOXARI A, DASKALOU E,
type amino acid transporter 1 (LAT1), 6. GALITA G, SARNIK J, BRZEZINSKA O et al.: GRAMMATIKOPOULOU MG, SKOUROLIA-
strongly expressed by synovial CD4+ Polymorphisms in DNA repair genes and as- KOU M, BOGDANOS DP: Mediterranean diet
T cells of patients with active RA, sociation with rheumatoid arthritis in a pilot and physical activity nudges versus usual
study on a Central European population. Int care in women with rheumatoid arthritis:
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tory parameters as well as DAS-28 https://doi.org/10.3390/ijms24043804 trolled trial. Nutrients 2023; 15(3): 676.
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Over the last year, several research 41(7): 1396-408. https:// tion: randomized trial. Rheumatology (Ox-
studies have been published shed- doi.org/10.55563/clinexprheumatol/oqu492 ford). 2023; 62(2): 565-74. https://
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Identifying shared genetic architecture be-
mechanisms underlying RA. In par- tween rheumatoid arthritis and other condi- signature of healthy lifestyle and risk of rheu-
ticular, studies on genetic, epigenetic tions: a phenome-wide association study with matoid arthritis: observational and Mendelian

1712 Clinical and Experimental Rheumatology 2024

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