ArticlePDF AvailableLiterature Review

Comprehensive insights into rheumatoid arthritis: Pathophysiology, current therapies and herbal alternatives for effective disease management

March 2024
Phytotherapy Research 38(6)

March 2024
38(6)

DOI:10.1002/ptr.8187

Authors:

Amrita Chatterjee

Indian Institute of Technology (ISM) Dhanbad

Monisha Jayaprakasan

Indian Institute of Technology (ISM) Dhanbad

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Rheumatoid arthritis is a chronic autoimmune inflammatory disease characterized by immune response overexpression, causing pain and swelling in the synovial joints. This condition is caused by auto-reactive antibodies that attack self-antigens due to their incapacity to distinguish between self and foreign molecules. Dysregulated activity within numerous signalling and immunological pathways supports the disease's development and progression, elevating its complexity. While current treatments provide some alleviation, their effectiveness is accompanied by a variety of adverse effects that are inherent in conventional medications. As a result, there is a deep-rooted necessity to investigate alternate therapeutic strategies capable of neutralizing these disadvantages. Medicinal herbs display a variety of potent bioactive phytochemicals that are effective in the complementary management of disease, thus generating an enormous potency for the researchers to delve deep into the development of novel phytomedicine against autoimmune diseases, although additional evidence and understanding are required in terms of their efficacy and pharmacodynamic mechanisms. This literature-based review highlights the dysregulation of immune tolerance in rheumatoid arthritis, analyses the pathophysiology, elucidates relevant signalling pathways involved, evaluates present and future therapy options and underscores the therapeutic attributes of a diverse array of medicinal herbs in addressing this severe disease.

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REVIEW

Comprehensive insights into rheumatoid arthritis:

Pathophysiology, current therapies and herbal alternatives

for effective disease management

Amrita Chatterjee

| Monisha Jayaprakasan

| Anirban Kr Chakrabarty

Naga Rajiv Lakkaniga

| Bibhuti Nath Bhatt

| Dipankar Banerjee

Avinash Narwaria

| Chandra Kant Katiyar

| Sunil Kumar Dubey

Department of Chemistry and Chemical Biology, Indian Institute of Technology (Indian School of Mines), Dhanbad, India

R&D Healthcare Division, Emami Ltd, Kolkata, India

Correspondence

Sunil Kumar Dubey, R&D Healthcare Division,

Emami Ltd, Kolkata 700056, India.

Email: sunilbit2014@gmail.com

Funding information

Science and Engineering Research Board,

Grant/Award Number: SRG/2022/000091

Abstract

Rheumatoid arthritis is a chronic autoimmune inflammatory disease characterized by

immune response overexpression, causing pain and swelling in the synovial joints.

This condition is caused by auto-reactive antibodies that attack self-antigens due to

their incapacity to distinguish between self and foreign molecules. Dysregulated

activity within numerous signalling and immunological pathways supports the dis-

ease's development and progression, elevating its complexity. While current treat-

ments provide some alleviation, their effectiveness is accompanied by a variety of

adverse effects that are inherent in conventional medications. As a result, there is a

deep-rooted necessity to investigate alternate therapeutic strategies capable of neu-

tralizing these disadvantages. Medicinal herbs display a variety of potent bioactive

phytochemicals that are effective in the complementary management of disease, thus

generating an enormous potency for the researchers to delve deep into the develop-

ment of novel phytomedicine against autoimmune diseases, although additional

evidence and understanding are required in terms of their efficacy and pharmacody-

namic mechanisms. This literature-based review highlights the dysregulation of

immune tolerance in rheumatoid arthritis, analyses the pathophysiology, elucidates

relevant signalling pathways involved, evaluates present and future therapy options

and underscores the therapeutic attributes of a diverse array of medicinal herbs in

addressing this severe disease.

Abbreviations: ACPA, anti-citrullinated protein antibody; APC, antigen-presenting cells; BCR, B-cell receptor; bDMARDs, biological DMARDs; CAR-T cell, chimeric antigen receptor-T cell; CD,

cluster of differentiation; CIA, collagen induced arthritis; COX, cyclooxygenase; CRP, C-reactive protein; CSF, colony stimulating factor; CTLA, cytotoxic t lymphocyte antigen; DC, dendritic cells;

DCM, dichloromethane; DMARDs, disease-modifying anti-rheumatic drug; ECM, extracellular matrix; ERK, extracellular signal-regulated kinase; FLS, fibroblast-like synoviocytes; FOXP3,

forkhead box P3; Fz, frizzled; GFR, growth factor receptor; GMSCs, gingiva-derived MSCs; HLA, human leukocyte antigen; IDO, indoleamine 2,3-dioxygenase; IFN, interferon; Ig,

immunoglobulin; IKK, inhibitor of κB Kinase; IκB, inhibitor of kappa-B; IL, interleukin; JAK, Janus kinase; LPS, lipopolysaccharide; LRP, low-density lipoprotein receptor-related protein; MAPK,

mitogen-activated protein kinase; MDSCs, myeloid derived suppressor cells; MEK, map kinase kinase; MEKK, MAP kinase kinase kinase; MHC, major histocompatibility complex; MMP, matrix-

metalloproteases; MMPs, metalloproteinases; mRNA, messenger RNA; MSC, mesenchymal stem cell; mTOR, mammalian target of rapamycin; NIK, NF-κB inducing kinase; NSAIDs, non-steroidal

anti-inflammatory drugs; PAD, peptidylarginine deiminase; PG, prostaglandin; PI3K, phosphatidylinositol 3-kinase; PIP, plasma membrane intrinsic protein; PPAD, Porphyromonas gingivalis PAD;

PTPN, non-receptor protein tyrosine phosphatases; RA, rheumatoid arthritis; RANK, receptor activator of nuclear factor—kappa beta; RF, rheumatoid factor; RNA, ribonucleic acid; sDMARDs,

synthetic DMARDs; SE, shared epitope; STAT, signal transducer and activator of transcription; T-reg, T-regulatory; TCF, transcription factor; TCR, T cell receptor; TGF, transforming growth

factor; Th, T-helper; TLR, toll-like receptor; TNF, tumour necrosis factor; TX, thromboxane; TYK, tyrosine kinase; VEGF, vascular endothelial growth factor; Wnt, Wingless-related integration site.

Amrita Chatterjee, Monisha Jayaprakasan, and Anirban Kr Chakrabarty contributed equally to this study.

Received: 1 November 2023 Revised: 14 February 2024 Accepted: 1 March 2024

DOI: 10.1002/ptr.8187

KEYWORDS

autoimmunity, herbals, inflammation, joints, rheumatoid arthritis, tolerance

1|INTRODUCTION

Rheumatoid arthritis (RA) is a systemic (van Delft & Huizinga, 2020),

chronic, inflammatory autoimmune disease (Giannini et al., 2020)

characterized by pain and swelling in the diarthrodial joints of the

body due to symmetric bone and articular cartilage destruction, lead-

ing to permanent loss of function and deformation of the joints (Bus-

tamante et al., 2017; Felix et al., 2021). This disease manifests in the

form of synovial hyperplastic inflammation, that is, hyperproliferation

of macrophage-like synoviocytes and fibroblast-like synoviocytes

(FLS) in the synovial membrane inside the joint capsule (Masoumi

et al., 2021; Mousavi et al., 2021). This condition witnesses a large

influx of immune cells like activated neutrophils, CD4

T cells, B cells

and macrophages into the inflamed synovium, along with a massive

production of matrix metalloproteinases (MMPs), collagenases, serine

proteases and aggrecanases that digest and disintegrate the articular

components of the joints (Abdel-Rafei et al., 2022; Guo et al., 2018).

In 2020, the global estimated number of people suffering from RA

was 17.6 million with a prevalence of 208.8 cases per million individ-

uals worldwide. The systematic analysis also reported a death rate of

0.47 per million, showcasing a 23.8% reduction in the last 30 years

(GBD 2021 Rheumatoid arthritis collaborators, 2023). Another study

reported the global average point and period prevalence of RA as

0.51% and 0.56%, respectively (Almutairi et al., 2021).

Scientific studies have established that RA has deep-seated early

signs of immune response much before the clinical onset of the dis-

ease. The rheumatoid factor (RF) and the anti-citrullinated peptide

antibodies (ACPAs) are the two categories of antibodies, which can be

detected in patients' sera as early as 14 years before the onset of clin-

ical RA symptoms. Magnetic resonance imaging scans and synovial

biopsy of ACPA and RF-positive patients with no history of RA, some

of whom developed RA symptoms eventually, have shown regular

healthy synovium. This suggested that autoimmunological responses

precede synovial inflammation in the progression of this disease,

which is an advantage in terms of pre-diagnosis and management for

individuals at risk of developing RA (Derksen et al., 2017; Scherer

et al., 2020). Researchers have concluded that a ‘second hit’is needed

to convert autoantibody presence to clinical inflammation (Petrovská

et al., 2021). Current treatment options for RA include non-steroidal

anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheu-

matic drugs (DMARDs) in combination with steroids (immunosuppres-

sants), biologics and surgery (Radu & Bungau, 2021; Sardana

et al., 2023). Recent therapeutic advances constitute mesenchymal

stem cell (MSC) therapy (Lv et al., 2021), dendritic cell (DC) therapy

(Alahdal et al., 2021; Han et al., 2020), adenosine augmentation and

T-cell modulation (Li & Chen, 2022). These therapies work by inhibit-

ing inflammatory responses at different levels of the immunological

cascades and targeting different immune cells involved in the

progression of the disease for instance pro-inflammatory cytokines,

cell surface receptors and adhesion molecules, B and T cells, chemo-

kines and cell signalling pathways. However, the success of these

treatment options is limited by adverse events, poor solubility, immu-

nogenicity (for biologics), toxicity, poor patient compliance, resistance,

and so forth. Therefore, there is an immediate need to develop more

efficient and highly specific immunomodulators (Bullock et al., 2019;

Costello et al., 2019). Anti-inflammatory and anti-arthritic herbs have

been used to treat various arthritis ailments for eternity. Over time,

mounting evidence highlights numerous herbs possessing anti-inflam-

matory potential, urging the scientific community to delve deeper into

this field (Ghasemian et al., 2016; Wang, Chen, et al., 2021). There are

several studies of the anti-rheumatic effects of East Asian herbal med-

icine showing anti-inflammatory activity comparable with current

drugs (Jo et al., 2022). The attention of the scientific community has

shifted from modern small-molecule drugs back to herb-derived medi-

cines in recent decades. Researchers are diving deep into phytochemi-

cals that can serve as safer, non-toxic, free from synthetic

constituents and efficiently soluble entities that can show effective

inhibition of pathogenic mechanisms of RA. It is high time that the

focus of pharmaceuticals is transitioned towards phytopharmaceutical

entities to establish non-invasive but efficacious therapeutic

regimens.

In this review, we have explored the mechanisms of the body's

immune tolerance. In addition, we've examined the breakdown of tol-

erance in the case of RA. Next, we have listed the signalling pathways

involved in the progression of RA, which are responsible for chronic

inflammation and damage to the synovial joints. Moreover, we've pro-

vided an overview of current treatment approaches for the manage-

ment of RA, followed by a discussion on emerging therapeutic

strategies that show promise for more effective management of the

disease. Finally, we've mentioned herbal sources and their potential

anti-inflammatory role in modulating immune responses and alleviat-

ing RA symptoms. This comprehensive perspective aims to promote

the utilisation of natural effective therapeutic sources towards

addressing this disease.

1.1 |Risk factors for RA

1.1.1 | Genetic factors

The human leukocyte antigen (HLA) allele plays a role in antigen pre-

sentation by antigen-presenting cells (APCs). This allele is found

within the major histocompatibility complex (MHC) and is responsible

for the expression of the MHC molecules on the cell surface for cell-

to-cell immune signalling functions like antigen presentation to T-cells.

The shared epitope (SE) of the HLA-DR beta locus is a specific genetic

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determinant for the ACPA phenotype of RA (Larid et al., 2021;

Wysocki et al., 2020). The peptide corresponding to the HLA/DR4/1

allele or the SE is responsible for presenting the autoantigen APC to T

lymphocytes (Jung et al., 2022; Zhuo et al., 2022). The non-HLA genes

associated with RA are constituted by the peptidylarginine deiminase

(PAD)-I4, CD28 and LIMK1 (Mathebula et al., 2022). Genetic varia-

tions, especially single nucleotide polymorphisms of non-receptor pro-

tein tyrosine phosphatases 22 (PTPN22), cytotoxic T lymphocyte

antigen 4 (CTLA4) and PADI4 genes have been associated with the

risk of developing RA (Padyukov, 2022). These are the genetic predis-

positions that dictate the chances of developing RA in most cases.

1.1.2 | Epigenetic factors

Epigenetics forms the bridge between genetically inherited

factors leading to causative roles and environmental stimulations

manifesting the disease. Although this makes comprehension of the

disease more complex, it is important to point out that these different

aspects crosstalk with each other during the development of

RA. Researchers have shown that epigenetic alterations are associ-

ated with RA through RA FLS, where these hyperplastic cells show-

case a unique deoxy ribonucleic acid hypomethylation pattern in the

early onset RA that evolves as the disease progresses. The hypo-

methylation was observed in the promoter of the C-X-C motif ligand-

12 gene and long interspersed nuclear element-1 retrotransposons,

which are normally repressed by deoxy ribonucleic acid methylation.

Histone acetylation in the nuclei of RA FLS is also abnormal due to

disharmony between acetylation enzymes like histone acetyltrans-

ferases and histone deacetylase. Micro-ribonucleic acids (micro-RNAs)

and other non-coding RNAs exhibit disorganized erratic expression in

FLS (Glant et al., 2014; Karami et al., 2020). These epigenetic modifi-

cations may determine the possibility of suffering from this chronic

disease.

1.1.3 | Gender

Autoimmune disorders portray an evident gender bias with a preva-

lence twice in women as compared to men. Pregnancy, menopause

and other hormonally critical and stressful stages make women vul-

nerable to distortions of immune regulation (Angum et al., 2020; Ngo

et al., 2014). This gender disparity in the prevalence of autoimmune

diseases is attributed to sex hormone-dependent signalling, and the

complex expression of genes encoded on the X chromosome

(Yuen, 2020). The prevalence of RA in women is approximately three

times more than that in men (Dedmon, 2020; Maranini et al., 2022).

Hormones and cytokines evidently affect bone metabolism (Bertoldo

et al., 2021). Sex hormones such as oestrogens, androgens and prolac-

tin have been associated with immune responses and rheumatic dis-

eases (Raine & Giles, 2022). Women are at a greater risk of

developing autoimmune disorders, especially between ages 40 and

60, when the female body undergoes significant menopausal

hormonal alterations (Shah et al., 2020). Menopausal women suffering

from RA are associated with an increased deterioration in joint func-

tionality, as compared to women in pre-menopausal or post-meno-

pausal age groups (Mollard et al., 2018; Ramachandran et al., 2023).

In RA, decreasing oestrogen and progesterone levels during meno-

pause might aid the pathogenesis of the disease since these hor-

mones have anti-inflammatory and protective effects on bones and

joints (Angum et al., 2020). The difference in the complex interactions

between genes, environment and hormones may cause increased dis-

ease activity in women (Carmona et al., 2023). This is how gender

plays a role in the risk of development and severity of disease

manifestation.

1.1.4 | Lifestyle-related and environmental factors

Smoking is an environmental trigger that invokes the risk of the devel-

opment of RA and is one of the leading causes of RA mortality (Gwin-

nutt et al., 2020; Ishikawa & Terao, 2020). Smoking leads to

subsequent asthma and chronic obstructive pulmonary disorder,

which increases the risk of developing RA (Ford et al., 2020). Accord-

ing to a study, there is an independent correlation between the risk of

developing RA and the presence of DRB1-SE genes in a patient's

genome as well as with patients having a smoking habit. Moreover,

there is a greater relative risk of developing RF-seropositive RA in

smokers having the SE gene by more than two times as compared to

the independent relations (Padyukov et al., 2004). A study proved that

hydroquinone, a benzene metabolite present in cigarettes deteriorates

RA conditions and worsens the chronic inflammatory conditions of

the body (Heluany et al., 2018). Along with smoking, obesity is a con-

tributing risk factor to the development of RA (De Hair et al., 2012).

Adipocytes, or fat-storing cells, secrete chemicals called adipokines,

which can upregulate pro-inflammatory mediators such as T cells, B

cells, macrophages, neutrophils, DCs and a repertoire of pro-inflam-

matory cytokines, which is why obese RA patients have more severe

conditions and altered response profiles to treatment (Poudel

et al., 2020; Tang et al., 2021). Scientists have identified obesity as an

inflammatory state and associated it with increased pain, inflamma-

tion, comorbidities and treatment failure (Kadhim, 2023). Diabetes is

also associated with the development of RA. A 51% of recent onset

RA patients and 58% of long-term RA patients developed insulin resis-

tance, which is also correlated with obesity and adipose content. Insu-

lin resistance was reported higher in RA patients than in non-RA

patients (Giles et al., 2015). Since Type 1 diabetes is also autoimmune,

it was hypothesized that the genetic determining factors of these two

diseases arising from genes like HLA-DRβ1, PTPN22, CTLA-4, inter-

leukin (IL) 23 receptor, tyrosine kinase 2 (TYK2) and T cell activation

rho GTPase activating protein may have conjoint aspects (Nicolau

et al., 2017; Theofilopoulos et al., 2017). Inhalation of notorious che-

micals like smoke, silica dust, nano-sized silica and carbon-based

nanoparticles has exhibited activation of mucosal toll-like receptors

(TLRs) that activate PAD enzymes leading to unusual citrullination,

dendritic and B cells (Guo et al., 2018). Diet has also been associated

CHATTERJEE ET AL.3

with RA (Rondanelli et al., 2021). Foods containing Porphyromonas gin-

givalis, high-fat content and plant-derived lectins can trigger ACPA

production (Skoczyńska & Swierkot, 2018). Emphasis on the impor-

tance of one's environment and daily habits is a concept that holds no

novelty. The discussed lifestyle-related causes may play a massive role

in the break of tolerance and subsequent deterioration of joint health

in RA. It is very important to lead a holistically healthy life to prevent

the onset of diseases such as RA.

1.1.5 | Pathogenic factors

Microbial infections like P. gingivalis, Epstein–Barr virus, Aggregatibac-

ter actinomycetemcomitans,Proteus mirabilis and mycobacteria are

known to trigger the onset of RA (Bo et al., 2020; Bourgeois

et al., 2019). These organisms are capable of encouraging peptide-

citrullination and the development of ACPAs. It is reported that

P. gingivalis synthesizes the PAD enzyme, which makes it a major

pathogen capable of inflicting the disease. P. gingivalis biofilm was pro-

nounced in RA patients suffering from periodontitis and synovial fluid

samples of RA patients also showed the presence of the microbe

(Ahmadi et al., 2023; Li et al., 2022). A correlation was found between

anti-P. gingivalis PAD (anti-PPAD) immunoglobulin G (IgG) and anti-

cyclic citrullinated peptide IgG, and among anti-PPAD, C-reactive

protein and IL-6, indicating a causative role of PPAD in RA peptide

citrullination and systemic inflammation (Shimada et al., 2016). The

pathogen that causes periodontitis, A. actinomycetemcomitans,

secretes a toxin, leukotoxin A, which can cause abnormal citrullination

of antigens in the RA-affected joint and can also alter the neutrophil

structure in the synovium (Konig et al., 2016). An imbalance in the

homeostasis of the gut microbiome can have detrimental effects on

various pro-inflammatory and immune pathways (Coradduzza

et al., 2023). Hence, pathogenic factors should be considered with

equal importance while discussing risk factors for RA.

Figure 1consolidates the risk factors of RA and the consequent

symptoms that gradually manifest after the onset of the disease.

FIGURE 1 Causes and consequences of rheumatoid arthritis (RA).

4CHATTERJEE ET AL.

2|INTERPLAY OF TOLERANCE AND

AUTOIMMUNITY

Immunological tolerance is an intricate set of processes that facilitate

non-responsiveness to autoantigens in the body. Tolerance is classi-

fied based on location into central and peripheral tolerance (Wald-

mann, 2016). T and B cells both originate in the bone marrow, while T

cells are transported to the thymus for maturation (Brugman

et al., 2015; Owen et al., 2019), B cells remain in the marrow and tol-

erance is mainly regulated in these organs (Theofilopoulos

et al., 2017). When an antigen encounters an APC, there are three

possible fates that it can undergo: (1) non-recognition by the immune

cell if the antigen is non-immunogenic (ignorance), (2) recognition and

clonal expansion of the lymphocyte if the antigen is immunogenic

and (3) anergy which is the suppression of any immune response (neg-

ative selection; Yang et al., 2020).

It is well established that the body produces auto-reactive B and

T cells under normal conditions, but these entities are either removed

or suppressed through a variety of regulatory mechanisms like anergy

(non-responsiveness by inactivation) and deletion in both primary and

secondary lymphoid organs to render them harmless (Jumbo, 2021).

Auto-reactive B cells produce poly-reactive natural autoantibodies

that circulate in the normal human serum. These antibodies play an

important role in maintaining immunological homeostasis and mediat-

ing innate responses due to their broad specificity against antigens

(Miossec, 2022). Further, we delve into details about the two major

mechanisms of the development of immune tolerance.

2.1 |Central tolerance

In central tolerance, a collection of lymphocytes of both types: B and

T cells are generated that contain specific receptors for all the proba-

ble types of antigens that may encounter the immune system. B cell

surface receptors, or Igs and T cell receptors (TCRs), upon MHC pep-

tide presentation and co-stimulation, can respond to antigens. The

thymic training of T lymphocytes is divided into two phases. The initial

part occurs in the cortex where T cells undergo positive selection. The

T lymphocytes are constantly presented with self-antigens and

the ones that do not show any response eventually die (death by

neglectAlberti & Handel, 2021). The next phase takes place as the sur-

viving cells migrate to the medullary area of the thymus and are pre-

sented with peptide–MHC complexes by thymic medullary epithelial

cells that serve as APCs (Owen et al., 2019). The immune cells that

show recognition and elicit an immune response against these self-

peptides are eliminated (negative selection; Theofilopoulos

et al., 2017).

The thymus releases both self-reacting T cells and T-regulatory

(T-reg) cells, the latter being in quantitative excess. Early research on

tolerance suggested that self-antigens were simply ignored by auto-

reactive immune complexes (Wing & Sakaguchi, 2010). The discovery

of T-reg cells brought a different aspect of tolerance into the picture

where T-reg cells actively suppressed the autoantibodies that would

otherwise respond to autoantigens in circulation. Tipping the balance

in favour of T-reg cells by suppressing T-effector cell-stimulating

cytokines can prove to be an effective strategy for the alleviation of

autoimmunity (Ni et al., 2019).

Researchers have identified a gene called autoimmune regulator

that plays an important role in medullary thymic epithelial promiscu-

ous gene expression, crucial for central tolerance. This gene can regu-

late the transcription of certain proteins that are expressed and used

for antigen presentation during thymic training (Shevyrev et al., 2022;

Theofilopoulos et al., 2017; Ucar & Rattay, 2015).

B cell central tolerance comprises apoptosis of B cells that show

reactivity towards self-antigens in the bone marrow or modification

of the B-cell receptor (BCR) to render it non-reactive towards the

self-peptide, a process known as receptor editing (Castañeda

et al., 2021). Tolerance occurs in two phases: passive tolerance that

comprises anergy of autoreactive B lymphocytes and active toler-

ance that consists of CD4

T cell-mediated suppression of autoreac-

tive B lymphocytes. B cell development witnesses gene

rearrangement to express a repertoire of specific Igs (Meng

et al., 2023). Auto-reactive B cells are eliminated (negative selection)

in these ways during maturation in the bone marrow before they

develop into naïve B cells (Singh et al., 2021). Central B-cell tolerance

is controlled by BCR and TLR signalling. An abnormal PTPN22 gene

causes anomalous BCR signalling (Yap et al., 2018). IL-2 cytokine pro-

duction stimulates the differentiation of naïve T cells into T effector

cells. After this, they are released and exported for exhibiting periph-

eral tolerance (Kumar et al., 2018). Central tolerance is thus the pri-

mary process undertaken by our body to evade the occurrence of

autoimmunity.

2.2 |Peripheral tolerance

Despite the rigorous training at the thymus, some auto-reactive lym-

phocytes still bypass elimination and are released into the circulation

(Gallegos & Bevan, 2006; Theofilopoulos et al., 2017). These are kept

in check by peripheral tolerance that takes place in secondary lym-

phoid organs. Peripheral tolerance of B cells mainly occurs in two

ways: the B cells come across self-peptides but are not activated due

to the absence of activator T helper cells, or second, partially activated

B lymphocytes are excluded from the follicles (Singh et al., 2021).

There are three mechanisms of T cells exhibiting peripheral tolerance:

anergy, deletion and immune suppression. Anergy can be demon-

strated by two pathways, the first being the lack of co-stimulators

such as CD80/CD86 on the non-professional APC or CD28 on the T-

helper (Th) cell, leading to failure of T cell activation. The aftermath of

this phenomenon is that the T helper cell will not be activated even

on subsequent encounters with that specific antigen. The second

mechanism of anergy comprises CTLA-4 suppressor co-stimulation

instead of activator CD28 by the respective APC, rendering the Th

cells as merely persisting functionally inactive cells. The deletion

method is characterised by caspase-induced apoptotic Th cell death

due to over-activation by high antigen concentration, called

CHATTERJEE ET AL.5

activation-induced cell death, mediated by the Fas (CD95) ligand and

receptor. The final mode of peripheral tolerance, immune suppression,

is exhibited by the T-reg cells, which were initially named T-suppres-

sors (Owen et al., 2019). T-reg family of cells exist in the form of some

subtypes. The first is natural T-regs that express CD4, CD25, forkhead

box P3 (Foxp3), CTLA-4 and membrane transforming growth factor

(TGF)-β. They do not produce cytokines and show immune suppres-

sion by a cell-contact-dependent mechanism. The second type of Treg

cells is called adaptive Treg cells, which are further classified into

(1) Th3 cells that act by producing soluble TGF-β, and (2) Tr1 cells that

are induced by the presence of, and produce IL-10, and do not

express Foxp3. These adaptive Treg cells are found in the periphery

which also act through TGF-βand IL-10 (Meng et al., 2023). Peripheral

T-cells consist of naïve T cells, memory T cells and Treg cells having

different immune functions (Kumar et al., 2018). Autoreactive B cells

are removed from the B cell repertoire by undergoing deletion in the

T cell zones of the spleen and lymph nodes. Loss of B cell tolerance is

believed to occasionally result from a lack of assistance from T lym-

phocytes, especially T-reg cells (Kamradt & Mitchison, 2001; van de

Veen et al., 2016). This is how the event of peripheral tolerance works

to prevent the possibility of the development of autoimmune

conditions.

2.3 |Loss of tolerance and development of

autoimmune diseases

The tolerance-related process of auto-reactive T lymphocytes getting

deleted, inactivated or anergised, commences shortly after birth and

this is how any autoimmune conditions are prevented. These mecha-

nisms are referred to as recessive tolerance actions that alleviate the

odds of highly auto-reactive lymphocytes being circulated. However,

self-reactive lymphocytes with low affinity for autoantigens might

escape these measures and need a more dominant arsenal like Foxp3

T-reg cells to be silenced. Studies have shown that autoimmune dis-

eases display variations of IL-2, its receptor IL2RA, tumour necrosis

factor (TNF) alpha induced protein 3 and CTLA4, which can poten-

tially disrupt usual T-reg manufacture and activity and aggravate the

inflammatory environment (Law et al., 2014).

Scrutinized research has highlighted a subset of IL-10 and TGF-

βsecreting CD1d CD5

B cells called B-regulatory or B10 cells that

develop in the spleen upon IL-21 stimulation. These cells are trig-

gered by lipopolysaccharide (LPS) and TLR4, are predominantly pre-

sent in aged mice and can be activated irrespective of T cell

presence in the proximity of a diversity of BCRs, pointing towards

the activity of these cells in autoimmune circumstances. These cells

were considered to modulate T-reg cell activity as well as Th cell

polarizations (Luu et al., 2014). Despite these tolerance mechanisms

set in place, the body might overcome them to lead to autoimmu-

nity. The probable causes for this are the variable extent of intrathy-

mic deletion of autoimmune T cells and the activation of self-

reactive T cells upon interaction with pathogenic entities

(Jumbo, 2021).

2.4 |Loss of tolerance in RA

T-reg cells are vital for peripheral immune tolerance, and their dys-

function has been associated with the onset of autoimmune disorders

like RA due to the imbalance of T-reg and self-reactive T-effector

cells. One of the characteristic features of RA is the presence of RF in

the serum of the patient. This antibody is sensitive to the fragment

crystallizable region of the IgG antibodies (Kuligowska-Prusińska &

Odrowąż-Sypniewska, 2018; Yamada et al., 2005). It is known that

IgG acts as an autoantigen in this autoimmune condition. More

recently, however, the focus has shifted to citrullinated proteins as

the actual autoantigens triggering the onset of RA (Wegner

et al., 2010). According to a study, B lymphocytes have a pivotal role

in the progression of RA. B cells, demonstrate an over-expression of

HLA-DR cell surface marker (needed for auto-antigen presentation)

and CD22 (BCR co-receptor) in seropositive RA patients. The sera of

RA patients were found to contain abnormally high levels of memory

B cells, IgM and IgA antibodies (Wang et al., 2019). In RA, both central

and peripheral tolerance checkpoints are aberrant, resulting in an

excessive generation of autoreactive mature naïve B cells. This causes

T-reg cell dysregulation and the generation of polyreactive autoanti-

bodies, resulting in B cell evading suppression and apoptosis. B cells

also exacerbate T cell differentiation into memory cells (Yap

et al., 2018). However, it is not clear what causes the transition of

ACPA presence to clinically evident RA. The exact trigger for the

break of tolerance against self-antigens needs more clarity and is

surely multifaceted, but is associated with genetic, pathogenic, envi-

ronmental and lifestyle-related factors (Catrina et al., 2021; Page

et al., 2021). The mechanisms of central and peripheral tolerance of

both B and T lymphocytes are depicted in Figure 2, along with the

break of immunological tolerance and generation of autoantibodies in

RA-affected patients.

3|PATHOPHYSIOLOGY AND DISEASE

PROGRESSION OF RA

RA manifests in three consecutive stages: pre-clinical or triggering

stage RA, early ‘clinically evident’RA and chronic ‘established’RA

(Singh et al., 2022). Pre-clinical RA encompasses autoimmune priming

in healthy individuals, which is characterised by the detection of auto-

antibodies in the patient's serum (Greenblatt et al., 2020). The second

stage is the maturation stage where the joints are attacked by the vast

network of mediators of the immune system, though the specificity of

the type of ACPAs towards a certain inflammatory after-effect is yet

to be clearly understood. The final targeting stage represents chronic

inflammation, and most patients do not visit the clinic before the

arrival of this stage. The nature of this phase is progressive and

exhibits irreversible destruction and deformation of the affected joints

(Holmdahl et al., 2014; Yarwood et al., 2015).

A synovial joint or a diarthrosis enables smooth movement at the

junction of two or more cartilage-covered ends of bones by encapsu-

lation of the synovial cavity with a fibrous joint capsule that is

6CHATTERJEE ET AL.

continuous with the periosteum of the consecutive bones. The syno-

vial cavity contains synovial fluid, which lubricates the joint (Marian

et al., 2021). The synovial membrane lines the inner side of the cap-

sule and is composed of two layers: the intimal and the subintimal

layer. The intimal layer is further comprised of two types of cells—FLS

and macrophage-like synoviocytes (Kiener & Karonitsch, 2011). The

intimal stratum of the synovium contains spaces and lacks tight junc-

tions and desmosomes (Wu et al., 2021). The vascularised subintimal

layer composed of connective tissue is more tightly packed with little

room for porosity, consisting of macrophages, mast cells, adipocytes,

fibroblasts, lymphatic cells and nerve endings. FLS is responsible for

the maintenance of the synovial extracellular matrix (ECM) by secret-

ing matrix proteins such as fibronectin, collagens, tenascin, proteogly-

cans, laminins and ECM-degrading enzymes such as proteases, MMPs

and cathepsins. They also secrete hyaluronic acid as well as lubricin

for the lubrication of the joint (Nygaard & Firestein, 2020; Smith &

Wechalekar, 2015; Zhang et al., 2022).

In RA, the FLS undertake an aggressive phenotype and undergo

excessive proliferation as an inflammatory response (Masoumi

et al., 2020; Xu et al., 2019), probably because of MSCs in the syno-

vium, followed by aggregation of abnormal hyperproliferative FLS

(pannus). FLS secrete MMPs that manifest ECM destruction (Wu

et al., 2021). FLS also secrete a range of pro-inflammatory and pro-

angiogenic cytokines and chemokines, prostaglandins (PGs), cyclooxy-

genases (COXs) (Umar et al., 2012), which in turn trigger the recruit-

ment of other immune cells, such as neutrophils, macrophages and

fibroblasts, as well as B and T cells, which altogether activate destruc-

tive participants, such as osteoclasts to promote inflammation and

ultimately, joint destruction (Masoumi et al., 2020). Cartilage destruc-

tion and bone resorption take place because of the generation of

osteoclasts and chondrocytes. Under normal conditions, chondrocytes

secrete and maintain the components of the cartilaginous layer

(Prathap Kumar et al., 2020). This causes parts of the cartilage to wear

away and the bone to be exposed, causing friction, and aggravating

the pain and inflammation. The pannus infiltrates into the cartilage

and subchondral bone (Masoumi et al., 2021). Receptor activator of

nuclear factor—kappa beta (RANK)-induced differentiation of osteo-

blasts into osteoclasts and consequently bone resorption is regulated

by a family of transmembrane proteins called Siglecs or Sialic acid-

binding Ig-like lectins. These are expressed by immune cells and help

in the regulation of tolerance and bone homeostasis and can prove to

be effective targets for treatment against RA (Ye et al., 2023).

This condition originates from the immunological response of

autoantibodies against proteins that are citrullinated as a part of post-

translational modifications of proteins. Citrullinated proteins are char-

acteristic of inflammation, but the phenomenon of antibodies target-

ing these proteins is highly specific to RA (Vossenaar et al., 2003). The

positively charged amino acid arginine is converted to citrulline, a neu-

tral amino acid, by a subtype of enzymes called PADs in a calcium-

dependant reaction (Curran et al., 2020; Fuhrmann et al., 2015;

Yamada et al., 2005). PADs are secreted by granulocytes and macro-

phages present in the synovium. They can be of five isoforms: PAD1,

FIGURE 2 Tolerance mechanisms in healthy individuals and loss of tolerance in rheumatoid arthritis (RA)-affected patients. APC, antigen-

presenting cells; IgG, immunoglobulin G.

CHATTERJEE ET AL.7

PAD2, PAD3, PAD4 and PAD6 (Fuhrmann et al., 2015; Kuligowska-

Prusińska & Odrowąż-Sypniewska, 2018). It has been established that

dysregulated citrullination is the key driving factor for triggering

RA. The targets of these ACPAs are identified as proteins like vimen-

tin, α-enolase, fibronectin, heterogeneous nuclear ribonucleoproteins,

Epstein–Barr nuclear antigen-1, type II collagen, specific histone pro-

teins and fibrin (Curran et al., 2020; Darrah & Andrade, 2018; Guo

et al., 2018). Moreover, modified IgG can also trigger the production

of autoantibodies (Islam et al., 2018). Citrulline being a non-natural

amino acid is recognised as foreign, which leads to the generation of

several ACPAs (anti-citrullinated protein antibodies) that include but

are not limited to RFs, anti-perinuclear factor or anti-keratin antibody,

anti-Sa, anti-PAD antibodies, anti-cyclic citrullinated peptide, anti-car-

bamylated protein antibodies, anti-binding Ig protein antibodies, anti-

RA33 antibodies and anti-glucose-6-phosphate isomerase antibodies,

which are reported to respond to citrullinated self-antigens. These

autoantibodies form immune complexes and stimulate a cascade of

downstream immunological responses at the inflamed synovial layer.

The RF and the ACPA are the most prominent specific markers used

for the diagnosis of RA (Kelmenson et al., 2020; Schaller et al., 2001;

Steiner & Smolen, 2002; Yamada et al., 2005; Yee et al., 2015). How-

ever, a study established that the rate of destruction of the joints of

RA-diagnosed patients was not associated with the antibodies against

citrullinated proteins (Nieto-Colonia et al., 2008).

Earlier, there was evidence to believe that the progression of RA

was driven by the MHC class II region on the 6th chromosome (Strand

et al., 2007). A recent study has modified this hypothesis and has

shown how citrullination modulates the antigen processing and MHC

presentation of the proteins that could potentially serve as autoanti-

gens. The repertoire of peptides generated from the unmodified pro-

tein forms of vimentin, fibrinogen and heterogeneous nuclear

ribonucleoprotein after proteolysis by a cocktail of cathepsins (mim-

icking MHC class II-associated proteases) was observed to be differ-

ent than the PAD-citrullinated variations of the same proteins (Curran

et al., 2023).

The inception of RA is characterised by an elevated expression of

the inflammatory cytokine and chemokine profiles in the circulation

even before the detection of autoantibodies. The profile of these sig-

nalling molecules and their receptors such as IL-1β, IL-2, IL-1RA, IL-

17, IL-4, IL-15, TNF-α, interferon α(IFN), monocyte chemoattractant

protein-1, macrophage inflammatory protein-1αand IL-2R is altered

in the system, a clear indication of immune activation and the onset of

RA. Citrullination of peptides triggers the invocation of RFs and

ACPAs, two important diagnostic markers for RA. However, there is

also a subtype of RA patients who do not show ACPAs in their sys-

temic circulation (33% of RA patients), leading to two categories of

patients: the ACPA-seropositive and the ACPA-seronegative subsets

of patients. Citrullinated antigens can activate MHC class II co-stimu-

lated T cells that activate B cells to synthesize ACPAs (Radu

et al., 2022).

These factors cumulatively form an auto-antibody storm that

largely precedes the manifestation of joint symptoms of RA. ACPAs

are the evidence of loss of immunological tolerance. The

autoantibodies bind to the sensed antigens and form anti-antibody

complexes. These immune complexes bind to fragment crystallizable

receptors present on the surface of various immune cells and activate

the complement system, bridging the gap between the innate and

adaptive immune systems (Ji et al., 2002). Consequently, immune cells

namely B lymphocytes, T lymphocytes and macrophages are activated

to elucidate immune responses (Hogarth & Pietersz, 2012). These cells

can either already be present in the synovium or can enter the joint

from the peripheral blood. Like macrophages, B and T lymphocytes

also produce a range of cytokines and chemokines enhancing the pro-

gression of RA. B and T cells co-stimulate and communicate with one

another to secrete more cytokines. Synovial macrophages and fibro-

blasts metamorphosize into tissue-invasive cells and aggravate joint

inflammation. Auto-reactive B cells attack self-antigens and worsen

joint damage. TNF-α, IL-1, IL-6, IL-12, IL-15, IL-17 and IL-18 are pro-

inflammatory cytokines (Stolina et al., 2009) secreted by natural killer

cells, neutrophils, macrophages, monocytes, fibroblasts and mast cells,

which frequently dominate the anti-inflammatory cytokines IL-4, IL-

10 and IL-13's protective effects, leading to cytokine-mediated

inflammation. IL-17, secreted by CD4

Th17 cells, can give rise to

MMP1 and MMP3 secreted by FLS that participate in the degenera-

tion of the ECM, increasing immune cell infiltration into the synovium.

These cytokines also induce the activation of osteoclasts by acting as

ligands for the RANK receptor on the surface of osteoblasts, causing

bone-resorption activity (Molendijk et al., 2018; Yap et al., 2018). The

FLS in the synovial layer become hyper-inflamed during the progres-

sion of RA upon signalling from pro-inflammatory cytokines, resulting

in a pannus-like hyperproliferative lining. The increased volume of

cells breaks into the narrowing joint space and invades the cartilage,

damaging it (Abdel-Rafei et al., 2022). Integrin-related processes

emerge, upregulating proliferative and infiltrative cellular pathways

like the mammalian target of rapamycin (mTOR) pathway (Bustamante

et al., 2017). Thus, the progression of the disease is an extremely intri-

cate series of events whose cumulative effects result in the painful

manifestations of the disease. The pathophysiological changes seen in

RA have been demonstrated in Figure 3.

4|SIGNALLING CASCADES AND

CELLULAR CROSSTALK IN RA

Herein, we have described the different cell signalling pathways that

are directly involved and upregulated during the progression of

RA. All these pathways have also been represented in Figure 4.

4.1 |JAK–Signal transducer and activator of

transcription pathway

The Janus kinases (JAKs) belong to an intracellular protein family of

TYKs. The four subtypes—JAK1/2/3 and TYK2 associate with intra-

cellular domains of transmembrane cytokine receptors (Rapalli,

Waghule, et al., 2020). Two out of the four types of JAKs get

8CHATTERJEE ET AL.

activated at once and they recruit cytoplasm-residing signal trans-

ducer and activator of transcription (STAT) proteins (Tanaka

et al., 2022) that dimerize and get activated by phosphorylation, trans-

locate to the nucleus and regulate transcription. Different members of

the STAT family identified are STAT1/2/3/4/5a/5b/6 (Ivashkiv &

Hu, 2003). Research studies have shown that levels of native as well

as phosphorylated forms of the transcription factor (TCF) STAT3 are

substantially elevated in the cytokine-induced rheumatoid synovium,

and this phosphorylation process is JAK dependent. One of the con-

tributions of this cell-signalling pathway to RA progression is through

IL-17-induced STAT3 that elevates the production of anti-apoptotic

genes like B-cell lymphoma-2 and RA-FLS proliferation is aggravated.

JAK-inhibitors such as gefitinib, tofacitinib and baricitinib downregu-

lated STAT3 in the synoviocytes. The study went on to show that JAK

inhibitors expedite sodium nitroprusside-induced apoptosis in hyper-

plastic RA synovium, along with curtailing the thickening of the syno-

vial layer. Some JAK-inhibiting drugs also suppressed the generation

of vascular endothelial growth factor (VEGF)-A, a few MMPs and

cytokines like IL-6 and TNF, pointing to the role of the JAK–STAT

pathway in RA pathogenesis (Emori et al., 2020; Lee et al., 2013). The

JAK pathway is triggered by various pro-inflammatory cytokines and

the pathway in turn results in the production of more cytokines and

this vicious cycle contributes to the severity of the disease. This was

supported by observing the reduction in disease severity and joint

destruction on treatment with JAK inhibitors like tofacitinib and pefi-

citinib (Ishikawa et al., 2023). The profusion of cytokines that are cir-

culated during RA advancement is perceived by nociceptive receptors

and this phenomenon induces the sensation of pain. This pain is not

only due to inflammation but also indicative of the changes occurring

in the RA synovium that are partially caused by the JAK–STAT signal-

ling cascade (Simon et al., 2021). Hence, the JAK–STAT mechanism is

proved to have a primary function as the disease progresses.

4.2 |Stress-activated protein kinase/MAPK

pathway

Stress-activated protein kinase or mitogen-activated protein kinase

(MAPK) pathway is constituted by a cascade of kinases that are acti-

vated by stimuli such as growth factors, inflammatory cytokines,

FIGURE 3 Pathophysiology of rheumatoid arthritis. ACPA, anti-citrullinated peptide antibodies; APC, antigen-presenting cells; ECM,

extracellular matrix; IL, interleukin; MHC, major histocompatibility complex; MMP, matrix-metalloproteases; RF, rheumatoid factor; TCR, T cell

receptor; TGF, transforming growth factor; TNF, tumour necrosis factor.

CHATTERJEE ET AL.9

stress signals and G protein-coupled receptor agonists. These extra-

cellular signals stimulate the activation of MAPK kinase kinases that in

turn phosphorylate MAPK kinases, followed by phosphorylation of

different isoforms of MAPKs that facilitate the activation of certain

TCFs that mediate transcription of genes responsible for cell growth,

survival, differentiation and development (Pradhan et al., 2019). Raf,

Ras, Mos and MAP kinase kinase kinase (MEKK)1 and 4 are various

subtypes of MAPK kinase kinases that activate MAPK kinases like

MEKs. MEK1 and 2 further trigger extracellular signal-regulated

kinase 1 and 2 (ERK1 and 2), while MEK4, 7 and MEK3, 6 trigger apo-

ptotic mediators like JNK1, 2, 3 and p38 MAPKs, respectively (Morri-

son, 2012). Multiple studies have shown the connection between RA

and the MAPK signalling pathway. MEK4, MEK7 and JNK (c-Jun N-

terminal kinase) can be detected in the IL-1-induced RA synovium,

FIGURE 4 Cellular signalling pathways involved in the progression of rheumatoid arthritis. APC, antigen-presenting cells; ECM, extracellular

matrix; IFN, interferon; IKK, inhibitor of κB kinase; IL, interleukin; IκB, inhibitor of kappa-B; JAK, Janus kinase; LRP, low-density lipoprotein

receptor-related protein; MMPs, matrix metalloproteinases; RANK, receptor activator of nuclear factor—kappa beta; STAT, signal transducer and

activator of transcription; TCF, transcription factor; TLR, toll-like receptor; VEGF, vascular endothelial growth factor; Wnt, Wingless-related

integration site.

10 CHATTERJEE ET AL.

along with the phosphorylated (activated) forms of MEK4 and MEK7

with the help of western blotting and immunohistochemistry using

anti-MEK antibodies. MEK4, 7 and JNK form a complex called a signa-

losome localised in the RA FLS cytoplasm, part of these complexes

moving to the FLS nucleus after cytokine stimulation (Sundarrajan

et al., 2003). There is evidence that IL-22-induced osteoclastogenesis

is mediated through the MAPK pathway by phosphorylation of the

p38 kinase. On the other hand, the anti-inflammatory cytokine IL-25

downregulated this phosphorylation induced by IL-22 (Min

et al., 2020). The MAPK pathway induces apoptosis by activating cas-

pases through MAP kinases, JNK and p38. Liquiritin, a natural flavo-

noid derived from the roots of Glycyrrhiza uralensis, an Asian plant,

caused apoptosis in IL-1βinduced RA-FLS and inhibited inflammation,

angiogenesis by downregulating phosphorylated p38 and JNK (Zhai

et al., 2019). Conclusively, the MAPK pathway is a principal process

during the pathogenesis of RA.

4.3 |NF-κB pathway

The NF-κB complex is localised in the cytoplasm, comprised of sub-

units: NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB and c-Rel. This

complex is blocked by the inhibitor of kappa-B (IκB) family compo-

nents, which secludes the complex to the peripheral cytoplasm. The

pathway can be stimulated in two ways: canonical and non-canonical.

The canonical route encompasses stimuli-induced ubiquitin–proteo-

some mediated degradation of the IκB, releasing the NF-κB complex,

which is then free to translocate into the nucleus and perform tran-

scriptional regulation (Kunnumakkara et al., 2021). It is activated at

the cell membrane through receptors like TNF receptor, IL-1 receptor

(IL1R), TLR, BCR, TCR and growth factor receptors (GFRs). The degra-

dation of IκB is triggered by its phosphorylation by the inhibitor of κB

kinase (IKK) complex, which is stimulated by different effectors like

cytokines, growth factors, stress signals and microbial fragments. The

non-canonical pathway works slightly differently. It is stimulated by

the lymphotoxin-αand β, CD40 and B cell activating factor (Ramadass

et al., 2020). This pathway is characterised by the degradation of the

precursor protein of the NF-κB2, called p100. This protein is phos-

phorylated by the NF-κB inducing kinase in association with IKKα

(a subtype of IKK) and is eventually ubiquitinylated. Then, it

undergoes further maturation by alteration of its c-terminal IκB-like

conformation, followed by the generation of a non-canonical NF-κB

complex that translocates to the nucleus (Liu et al., 2017). The NF-

κB pathway affects the transcription of genes for cytokines such as

IL-1, IL-6 and TNF-α, which are known to be upregulated in RA

patients' serum. The NF-κB cascade is prompted by the RANK ligand–

receptor binding on cytokine signalling, which leads to osteoclasto-

genesis-mediated bone resorption. The RANK ligand, a member of

the TNF family, is secreted by activated T cells and is over-expressed

in RA FLS, consequently, NF-κB is hyper-activated in RA synovial tis-

sue (Ilchovska & Barrow, 2021). Therefore, the NF-κB pathway has a

predominant function during the development and advance-

ment of RA.

4.4 |mTOR/Aβt pathway

The phosphoinositide-3 kinase (PI3K)/Akt/mTOR pathway is a pivotal

signalling pathway for cellular maintenance responsible for regulating

cell growth, proliferation, differentiation, messenger RNA (mRNA)

ribosomal synthesis, angiogenesis, apoptosis and cellular homeostasis.

This pathway can be activated by a range of growth factors as well as

insulin, herceptin and glucose. The basic series of events in this path-

way comprises the growth factor-induced activation of membrane-

bound TYK, which leads to the stimulation of the PI3K through an

exchange of phosphate group with Kirsten rat sarcoma virus. PI3K is

responsible for phosphorylating plasma membrane intrinsic protein

1 to 3 (PIP2 to PIP3). This, or phosphorylated phosphoinositide-

dependent kinase-1, can stimulate Akt, producing activated mTOR,

which moves into the nucleus to trigger the transcription of growth-

related genes. mTOR is detected in the form of two complexes,

named mTORC1 and mTORC2. mTORC1 exists in combination with

regulatory-associated protein of mTOR and regulates translation initi-

ation protein 4E binding protein 1 and is also associated with ribo-

somal S6 kinase-1. Alternatively, mTORC2, together with a factor

called rapamycin-insensitive companion of mTOR, demonstrates

kinase activity. This pathway is regulated by a tumour suppressor lipid

phosphatase, phosphatase and tensin homolog, that suppresses con-

sequent phosphorylation of PIP3 (Malemud, 2015). Inhibition of the

mTOR pathway by mTOR inhibitor sirolimus (also called rapamycin,

after which the name mTOR is derived) attenuated paw swelling in

human-TNF transgenic mice, proving that mTOR is involved in inflam-

matory progression. Moreover, it downregulated the osteoclast levels,

cartilaginous destruction and bone erosion at the synovial site. Osteo-

clast survival was established to be mTOR dependent, owing to dimin-

ished mature osteoclasts when cultured in vitro in the presence of

sirolimus, M-colony stimulating factor (CSF) and the RANK ligand.

Downstream components of the mTOR cascade such as Akt, mTOR,

S6 and 4E-BP are in their active phosphorylated state in the induced

RA environment (Cejka et al., 2010). Thus, the mTOR signalling path-

way plays a major role in the disease progression of RA.

4.5 |Wingless-related integration site/β-catenin

pathway

The Wingless-related integration site (Wnt)/β-catenin intercellular sig-

nalling pathway is an evolutionarily conserved pathway that plays a

role in the survival, homeostasis, regeneration and sustenance of cells,

which is why it is responsible for the cell proliferation of FLS in the

RA synovial environment (Dinesh et al., 2020). The pathway is acti-

vated by glycoprotein ligands of the Wnt family secreted by certain

cells that are recognised by receptors on the respective receiving cells.

There are 19 Wnt ligands present in animals and respective receptor

proteins for these ligands: 10 heterodimeric frizzled (Fz) receptors,

along with 1 low-density lipoprotein receptor-related protein (LRP)-5

and LRP6 as co-receptors (Ma et al., 2020). This signalling mechanism

may undergo one of two pathways: the canonical (β-catenin-

CHATTERJEE ET AL.11

dependant) pathway or the non-canonical (β-catenin-independent)

pathway (Rim et al., 2022). The canonical pathway proceeds in the fol-

lowing manner: in the inactivated state, aberrant signalling is pre-

vented by phosphorylation and subsequent degradation of the main

effector protein, which is a transcriptional co-activator, β-catenin.

These receptor components do not exist in physical contact with each

other when the pathway is not active. The phosphorylation and prote-

olysis of cytoplasmic β-catenin are led by a multimeric destruction

complex comprised of axin, adenomatous polyposis coli, glycogen

synthase kinase-3βand casein kinase 1α(Lorzadeh et al., 2021). Wnt

ligand (namely Wnt1, Wnt2b, Wnt3a, Wnt10b and Wnt16) binding

facilitates dimerization of the Fz and LRP5/6 to form the Fz-LRP5/6

receptor complex, activating the pathway. This is followed by the

assembling of the destruction complex at the cell membrane, thus dis-

engaging the proteosome-dependant ubiquitylation process. Β-cate-

nin stabilises and accumulates in the cytoplasm, and consequently

regulates transcriptional activation with the help of TCF/lymphoid

enhancer-binding factor (Bian et al., 2020). β-catenin target gene acti-

vation dictates cell fate, survival, proliferation and stem cell differenti-

ation, especially bone tissue formation osteoblastic differentiation

(Sharma & Pruitt, 2020). The non-canonical Wnt cascade can be fur-

ther divided into the Wnt/planar cell polarity pathway and the Wnt/

pathway. The Wnt/Ca

pathway results in the discharge of

intracellular calcium and promotes calcium-dependant mechanisms,

while the Wnt/planar cell polarity pathway is responsible for the

development of cell polarity, cytoskeletal re-arrangement, cell migra-

tion and adhesion (Sánchez & Flores, 2023). Instead of LRP5/6, non-

canonical Wnt ligands (namely Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt7b,

Wnt10b and Wnt16) bind to different co-receptors like TYKs and

receptor TYK-like orphan receptor (Lojk & Marc, 2021). A study

proved that the neuron navigator 2, which is upregulated in RA

patients, aggravates the condition through the Wnt/β-catenin path-

way, by activating inflammatory mediators like IL-8, IL-1βand IL-6 at

mRNA levels (Wang, Li, et al., 2021). Wnt5a upregulates pro-inflam-

matory mediators such as IL-1β, IL-8 and IL-6 (Mahmoud et al., 2021).

Wnt5a is reported to promote migration and invasion of RA FLS and

stimulate the expression of IL-6, IL-8, C-X-C motif ligand-5, MMPs-

1,3,9 and 13 predominantly through the Wnt/Ca

pathway. This

pathway also interacts with other signalling entities like p38, ERK,

AKT and glycogen synthase kinase-3βto enhance FLS invasion into

the synovium (Trillo et al., 2020). This is how the Wnt/β-catenin path-

way contributes to the aggravation of RA.

4.6 |VEGF pathway

The glycoprotein family (VEGFs) is responsible for the formation of

new blood vessels, wound healing, endothelial proliferation and

embryonic development. These dimeric proteins are produced in

fibroblasts, endothelial cells, T cells, platelets, macrophages, smooth

muscle cells and neutrophils (Mumtaz & Hussain, 2020). Comprised of

five related forms, VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental

growth factor, this pathway regulates also regulates vessel

permeability and angiogenesis. These ligand isoforms form dimers

when active and bind to their respective TYK-like vascular endothelial

GFRs on the surface of endothelial cells. This dimerization and binding

process instigates a cascade of channels such as the MAPK, PI3K and

phospholipase c-γsignalling pathways through phosphorylation of

tyrosine residues in the intracellular domain of the transmembrane

receptors (Shaw et al., 2024; Wang, Bove, et al., 2020). In RA, VEGF

regulates synovial angiogenesis during the progression of RA through

the interaction between the RA-FLS and the human dermal microvas-

cular endothelial cells. The newly formed blood vessels help feed the

inflamed synovial mass, thus aggravating the proliferative process. In

addition, VEGF prevents synoviocyte apoptosis, controls osteoclast

differentiation, instigates RANKL secretion and activates IL-6 and the

JAK–STAT pathway (Van Le & Kwon, 2021). The circular RNA homeo-

domain-interacting protein kinase-3 is upregulated and plays an

important role in the pathogenesis of RA by induction of VEGF-medi-

ated angiogenesis (Zhang, Ma, et al., 2021). A research group sug-

gested that β-sitosterol, a plant-derived sterol, suppressed the

migration and proliferation of endothelial cells, thus arresting synovial

hyperplasia and joint destruction by inhibiting the VEGF signalling

pathway (Qian et al., 2022). Another study reported that a single

nucleotide polymorphism in the VEGF gene can increase the chances

of developing RA. While the allele A of VEGF was found to be harm-

ful, the occurrence of allele C was found to have a protective effect

against RA (Hussain et al., 2023). Clearly, the VEGF pathway plays a

substantial role in increasing the severity of the disease.

5|CURRENT TREATMENTS AND THEIR

LIMITATIONS

Herein, we present an overview of the conventional treatment strate-

gies and the associated adverse effects that these therapies cause.

Some commonly prescribed drugs of each therapeutic category and

their reported adverse drug reactions have been summarized in

Table 1.

5.1 |Non-steroidal anti-inflammatory drugs

NSAIDs exhibit anti-inflammatory activity through the inhibition of

COX enzymes (Willoughby et al., 2000), which exist in three isoforms:

COX-1, COX-2 and COX-3 (Chandrasekharan et al., 2002), as well as

by suppressing TNF-α, inducible nitric oxide synthase and phospholi-

pase A2 or phospholipase C. All of these membrane-bound COX

enzymes convert arachidonic acid into PGH2 via PGG2, which is

eventually transformed into PGs like PGD2, PGE2, PGF2 and PGI2

(prostacyclin) along with thromboxane TXA2, each responsible for dif-

ferent physiological responses (Dwivedi et al., 2015). While COX-1

acts as a housekeeping enzyme being synthesized under all conditions

and regulating mucosal gastroprotection, vasodilation, bronchocon-

striction and platelet accumulation, COX-2 is induced during pain,

pyrexia and inflammatory responses (Willoughby et al., 2000).

12 CHATTERJEE ET AL.

Commonly prescribed NSAIDs include phenoprofen, paracetamol

(acetaminophen), ibuprofen, indomethacin, ketoprofen, ketorolac,

paracetamol and naproxen. Some NSAIDs are COX-2 selective inhibi-

tors, while others work by non-specifically inhibiting both COX

enzymes (Liu et al., 2005). Therefore, it is logically inferred that gen-

eral NSAIDs perform their expected anti-inflammatory activity by

inhibiting COX-2, and the undesirable side effects arise due preven-

tion of COX-1 activity (Kumar Vishwakarma & Negi, 2020).

An accumulation of adverse drug reactions originates from the

consumption of NSAIDs, ranging from gastrointestinal bleeding, car-

diovascular complications, thrombo-genetic risks to convulsions (Liu

et al., 2005), bronchospasm, renal disturbance and surge in haemoglo-

bin A1c in Type 2 diabetes patients. Aspirin, a commonly prescribed

NSAID, causes gastrointestinal bleeding (Dwivedi et al., 2015). The

plethora of adverse events associated with NSAIDs ranges from mild

symptoms like heartburn, digestive issues and abdominal pain to seri-

ous conditions like gastroduodenal ulcerations causing bleeding, and

perforation that may manifest into mortality. COX-1 inhibition by

NSAIDs may even suppress protective mucosal flow and cause ische-

mic damage. Over recent years, the rate of hospitalisation and treat-

ment discontinuation has spiked due to these adverse events (Davis &

Robson, 2016; Vonkeman & van de Laar, 2010).

5.2 |Disease-modifying anti-rheumatic drugs

The European Alliance of Associations for Rheumatology recommends

DMARDs as the first line of treatment upon diagnosis of RA (Smolen

et al., 2020). DMARDs are a family of drugs intended for inflammatory

diseases such as RA, psoriatic arthritis and ankylosing spondylitis;

TABLE 1 Current therapeutic options in practise for management of rheumatoid arthritis and their reported adverse events.

Treatment Options Adverse events reported References

NSAIDs •Diclofenac

•Celecoxib

•Ibuprofen

•Indomethacin

•Ketorolac

•Naproxen

•Salsalate

•Gastrointestinal bleeding and ulceration

•Cardiovascular complications

•Risk of thrombosis

•Bronchospasm

•Renal impairment

•Heart burn

Davis and Robson (2016), Harirforoosh and

Jamali (2009), Jiang et al. (2012), Liu et al.

(2005), Vonkeman and van de Laar (2010)

DMARDs

(not including biological

DMARDs)

•Methotrexate

•Hydroxychloroquine

•Sulfasalazine

•Leflunomide

•Azathioprine

•Opportunistic infections

•Anorexia

•Erythema

•Ultra-violet sensitivity, blurred vision

•Venous thrombosis

•Neurological complications

•Cardiovascular difficulties

•Psoriasis

•Tuberculosis

•Cancer

•Methylenetetrahydrofolate reductase

gene polymorphism

Berkun et al. (2004), Caporali et al. (2008),

Dhir and Aggarwal (2012), Goodman

(2015b), Ramiro et al. (2014)

Corticosteroids •Prednisone

•Dexamethasone

•Hydrocortisone

•Betamethasone

•Osteoporosis

•Cataract

•Poor bone mineral density

•Cardiovascular risks: hypertension,

atheroschlerosis, myocardial infarctions,

cardiac failure

•Vulnerable to infections

•Psychiatric reactions

•Alopecia

•Diabetes mellitus, obesity

Ethgen et al. (2013), Luís et al. (2019); Mitra

(2011), Stone et al. (2021), Wang, Zhao,

et al. (2020), Warrington and Bostwick

(2006), Wilson et al. (2019)

Biologics •Etanercept

•Adalimumab

•Infliximab

•Rituximab

•Anakinra

•Increased susceptibility to infections

•Malignancies: lymphoma and skin cancer

Goodman (2015b), Scott (2012), Smolen

et al. (2020), Strand et al. (2007), Tarp

et al. (2017), Woodrick and Ruderman

(2011)

Surgery •Arthroplasty

•Arthrodesis

•Synovectomy

•Arthroscopy

•Joint infections

•Deep vein thrombosis

•Nerve and tissue damage

•Pulmonary embolism

•Ossification

Athanasiou (2022), Burn et al. (2018),

Goodman (2015a,2015b)

Abbreviations: DMARDs, disease-modifying anti-inflammatory drugs; NSAIDs, non-steroidal anti-inflammatory drugs.

CHATTERJEE ET AL.13

connective tissue abnormalities and some cancers. These immuno-

modulatory entities possess unique mechanisms of action, that is,

each DMARD alters immune responses through a different mechanis-

tic fashion. For example, methotrexate is a DMARD that mimics folic

acid structure that inhibits enzymes pivotal for de-novo nucleotide

biosynthesis, such as dihydrofolate reductase, thymidylate synthase,

aminoimidazole carboxamide ribonucleotide transformylase and

amido phosphoribosyltransferase. Aminoimidazole carboxamide ribo-

nucleotide transformylase has been postulated as the primary target

of methotrexate (Benjamin et al., 2022; Inoue & Yuasa, 2014).

DMARDs are broadly classified into biological DMARDs

(bDMARDs) and synthetic DMARDs (sDMARDs). bDMARDS are fur-

ther of two types: biological originator DMARDs and biosimilar

DMARDs. Similarly, sDMARDs can be subdivided into conventional

sDMARDs like methotrexate, sulfasalazine and targeted sDMARDs

which include the recently introduced Jak-inhibitor drugs (Köhler

et al., 2019). A systematic literature review revealed that adverse

effects of bDMARD treatments may range from opportunistic infec-

tions to cancer, neurological, cardiovascular and GI complications,

venous thrombosis, upregulation of hepatic enzymes and manifesta-

tion of psoriasis. sDMARD treatment also posed similar aftermaths

such as skin infections, tuberculosis, cancer, cardiovascular conditions,

GI perforation and neurological problems (Ramiro et al., 2014).

JAK inhibitors are kinase-inhibiting targeted sDMARDs capable

of inhibiting the JAK–STAT pathway, hence suppressing inflammation,

antibody generation, synovial hyperplasia and joint damage. JAK

inhibitors approved by the Food and Drug Administration for RA man-

agement are tofacitinib, upadacitinib, peficitinib, baricitinib and filgoti-

nib. Another similar molecule called ritlecitinib is currently undergoing

phase II clinical trials for this disease (Tanaka et al., 2022). These are

very potent molecules that inhibit the different JAKs and provide

effective arthritic and neuropathic pain relief within 24 h (Harrington

et al., 2020).

Adverse events associated with DMARDs resulting in cessation

of therapy include nausea, abdominal pain and rashes. Moreover,

symptoms that surfaced early within an average of 3.1 months were

sweating and anorexia while latent effects include erythema, sensitiv-

ity to the sun and blurred vision taking a period as long as

32.5 months (Aletaha et al., 2003). Treatment with methotrexate, a

common DMARD, has been associated with an increased risk of infec-

tions, especially in the urinary and respiratory tracts. Leflunomide

usage has also been reported to cause upper respiratory tract infec-

tions in 10% or more of the patient population, as well as demanding

hospitalisation due to pneumonia and tuberculosis manifestation

(Caporali et al., 2008).

5.3 |Corticosteroids

Glucocorticoids or corticosteroids are a predominant immunosuppres-

sive mode of treatment against inflammatory diseases like RA (Huovi-

nen et al., 2023). They mostly elucidate action by interacting with key

signalling receptors. It is also detected in free form or combined with

corticosteroid-binding globulin, or transcortin. The free steroid mole-

cules can passively transport across the biological membranes, and

bind to intracellular glucocorticoid receptors, and the bound forms

can affect ligand-dependant TCFs and modulate transcription, transla-

tion and other genetic modifications. The anti-inflammatory effect of

corticosteroids is mainly mediated by inhibition of cytokine, chemo-

kine and adhesion molecule production and activity (Stone

et al., 2021). Some steroids recommended in the RA treatment regi-

men are prednisone, betamethasone, dexamethasone and hydrocorti-

sone (Hecht, 2022).

Glucocorticoids projected negative effects on glucose and cortisol

metabolism, along with catabolic effects on bone growth (Huovinen

et al., 2023). Steroid use was reported to be associated with a higher

risk of decreased bone mineral density, vertebral deformity, bone frac-

ture and osteoporosis, the extent of which was dependent on collat-

eral parameters like age, steroid dose and body mass index.

Prednisone treatment was linked to increased cases of bone loss,

especially in post-menopausal women. A study inferred that women

RA patients on corticosteroid treatment had a higher chance of devel-

oping osteoporosis. Glucocorticoid treatment has also shown elevated

chances of cardiovascular risks in RF-seropositive RA patients in the

form of carotid plaques and arterial incompressibility, and these symp-

toms were not a result of RA disease manifestation. Hypertension,

myocardial infarction and cardiac failure were also associated strongly

with patients on a long-term regimen of medium steroidal doses (Eth-

gen et al., 2013).

5.4 |Biologics

Biologic agents targeted against pro-inflammatory cytokines and

mediators of immune flare-ups have revolutionised therapy for inflam-

matory disorders like RA. These specific modulators interfere with

selective niches of immune responses and thus produce a highly spe-

cific but powerful impact. The major classes of biologics currently

being recommended for RA therapy are TNF inhibitors (adalimumab,

certolizumab pegol, etanercept and infliximab), IL1R antagonists (Ana-

kinra, Canakinumab), CD30 chimeric monoclonal antibodies (brentuxi-

mab, vedotin), RANK inhibitors (denosumab), B cell CD20 inhibitors

(rituximab), T cell co-stimulation inhibitors (abatacept) and IL-6 inhibi-

tors (two available drugs, e.g., tocilizumab; Ramadass et al., 2020;

Scott, 2012). ABT-122, a bispecific Ig designed to inhibit TNF and IL-

17A, is yet to be approved and has undergone clinical trials on

patients showing insufficient response to methotrexate (Genovese

et al., 2018).

TNF-αis a vital upstream cytokine regulator having both auto-

crine and paracrine nature that in turn stimulates the release of vari-

ous other cytokines such as ILs, facilitating angiogenesis, cell adhesion

and infiltration in the RA synovium, partially mediated by the NF-ĸB

cascade (Jang et al., 2021; Lee, Lee, Kim, et al., 2008). Etanercept, a

dimeric fusion protein specific for TNF; Infliximab, a chimeric mono-

clonal antibody comprised of human constant and mouse variable

fragments and Adalimumab, another TNF targeting recombinant

14 CHATTERJEE ET AL.

human monoclonal antibody, are some examples of TNF-specific bio-

logics used in RA treatment. These medications are generally pre-

scribed to be administered in combination with conventional

DMARDs like methotrexate and have shown effective alleviation of

rheumatoid symptoms, and advancement of joint destruction with

improvement in joint mobility (Tak & Kalden, 2011). Generally, the

therapeutic targets of biological medications in inflammation are T

and B lymphocytes, as well as cytokines like TNF-α, IL-1β, IL-6 and IL-

15 (Strand et al., 2007; van Loo & Bertrand, 2023).

However, like all other modern medicinal therapeutic strategies,

biologics also pose a threat of adverse events. TNF-suppressors like

etanercept, infliximab and adalimumab increase the risk of serious

infections, making the situation more complex since TNF is a pivotal

component for tackling infections. Logically, the rate of viral and other

opportunistic infections arising in populations undergoing IL-6 and IL-

1 inhibitor treatment has shown high susceptibility to infections

owing to the functional similarity of these cytokines to TNF. Random-

ised controlled trials of some biological therapies also revealed a con-

cerning increase in the incidence of malignancies like lymphoma and

skin cancer (Woodrick & Ruderman, 2011).

5.5 |Surgery

A common surgical approach to RA is to perform arthroplasty or joint

replacement surgery. This is a complicated procedure due to eventual

comorbidities, immunosuppressive therapeutic schemes and deformi-

ties. According to a study, 58% of RA patients choose orthopaedic

surgery during their anti-rheumatic treatment, with five out of

100,000 RA patients undergoing arthroplasty (Goodman, 2015a). Sur-

gery is the last resort in terms of treatment of RA when all medica-

tions such as DMARDs, NSAIDs and biologics have failed to alleviate

the symptoms of RA (Athanasiou, 2022). The other surgical treatment

options are arthrodesis, synovectomy and soft tissue surgery. Non-

operative management by splints and supports is critical (Simmen

et al., 2008). Arthrodesis entails irreversibly fusing the bones and

removing the joint gap and is a preferred option for RA-affected

wrists (Lautenbach et al., 2013).

Patients undergoing total hip or knee arthroplasty are at an

increased risk of dislocation and prosthetic joint infection. In the case

of prosthetic introduction, bacteria can form biofilms promptly at the

bone–prosthesis junction with a polysaccharide matrix that is

immune-resistant, making arthroplasty patients a high-risk group for

joint infections. However, there have been advancements in the surgi-

cal sector such as prophylactic antibiotics and laminar airflow on the

wound to prevent contamination, reducing joint infection incidences

to a low 2%–2.4% (Goodman, 2015b).

6|NOVEL POTENTIAL THERAPEUTIC

STRATEGIES EMERGING AGAINST RA

New-age therapeutic interventions are surfacing with enhanced experi-

mental technologies over time. A 2022 study revealed the potential role

of a microbial dye in combination with multiple low doses of gamma

radiation exhibiting anti-inflammatory effects and reducing disease

severity in adjuvant induced arthritis rats (Abdel-Rafei et al., 2022).

Alternatively, nano-carriers have also been explored for drug delivery

against chronic inflammatory diseases (Oshi et al., 2022;Gorantlaetal.,

2020; Donthi et al., 2023). Recently, dendrimers have gained attention

for their narrow polydispersity index (Dubey et al., 2021). A dendrimer

containing aza bisphosphonate was found to specifically target mono-

cytes and osteoclasts and suppress inflammation in experimental arthri-

tis rat models (Hayder et al., 2011). Micro-RNAs are also being explored

as potential targets in different diseases, as they regulate cell prolifera-

tion, differentiation and maintenance (Singhvi et al., 2018). These

instances bring scope for newer innovative inventions against RA that

are different from conventional treatment methods. Here, we elaborate

on some research phase therapeutic approaches that show immense

promise in evolving into established treatments.

6.1 |Myeloid-derived suppressor cells-based

therapy

Myeloid derived suppressor cells (MDSCs) are an assembly of heter-

ogenous immature immunosuppressive cells of myeloid origin gener-

ated in the bone marrow. They are classified into polymorphonuclear

(or granulocytic) and monocytic MDSCs (Ben-Meir et al., 2022). Iden-

tified in the 1990s, these cells can be produced and invoked by

pro-inflammatory mediators like granulocyte-CSF, macrophage-CSF,

granulocyte-macrophage-CSF, IL-1β, and IL-6. These immunomodula-

tors can inhibit T-cell mediated immune responses regulate B-cell

activity and be upregulated in the circulation of RA patients (Li

et al., 2021). Hyper-activity of MDSCs is associated with upregulated

granulocyte-macrophage-CSF and IL-6 production. Both types of

MDSCs express surface CD11b surface markers (Tamadaho

et al., 2018). MDSCs were evidenced to have a negative correlation

with activated Th-17 cells in the peripheral blood, indicating that

MDSC might have a role in inhibiting pro-inflammatory Th-17 cells

(Jiao et al., 2013; Park & Kwok, 2022). Detected in the synovial

region, these cells have a neutrophil-like structure and are potent T

cell inhibitors and prevent T cell infiltration into the synovium. So, an

increase in MDSC levels at the site of inflammation is desired and can

be a therapeutic strategy against RA (Kurkó et al., 2014). Male DBA/1

strain of mice induced with arthritis using CFA were used to study the

behaviour of MDSCs in autoimmune arthritis. The study demon-

strated that CD11b +Gr-1 +MDSCs accumulate in murine spleen

after induction of arthritis, suppress CD4

T cell expansion and pro-

inflammatory cytokine release, in case of malignancies as well as auto-

immune conditions (Fujii et al., 2013). An attempt at a deeper under-

standing of the mechanistic effect of MDSCs led to the fact that

granulocytic-myeloid-derived suppressor cells release exosomes con-

taining various immunoregulatory molecules, which could decrease

immune aggravation by stimulating B cells to produce anti-inflamma-

tory cytokine IL-10, both in vitro and in vivo. This led to a decrease in

activated plasma and Th cells in the lymph nodes of collagen-induced

arthritis (CIA) mice models (Wu, Zhu, et al., 2020).

CHATTERJEE ET AL.15

6.2 |T-cell targeted therapy

T cells play a vital role in the advancement of RA. CD4

T cells pre-

dominantly invade the synovial space and aggravate inflammatory

conditions. They trigger multiple signalling pathways offering both

pro-inflammatory and anti-inflammatory responses, i.e., they have a

regulatory role in autoimmune diseases. Cytotoxic T lymphocytes are

amply detected in the RA synovium. A strategy to control the differ-

entiation and functionality of T cells can be a potential treatment for

RA, by inducing the disease-suppressing functions and inhibiting the

disease-aggravating properties (Ni et al., 2019). Cytotoxic T lympho-

cytes are amply detected in the RA synovium. Several T-cell targeted

therapies have been proposed to modulate the functionalities of T

lymphocytes in the body for a desired activity, targeting T-cell surface

markers, TCRs, co-stimulatory cell surface factors, T-cell GFRs and T-

cell-produced cytokines (Weyand & Goronzy, 2006). For example,

cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig), a fusion

protein, is the initial member of a new family of medications called co-

stimulation blockers that is being tested for the management of

RA. APCs' co-stimulatory cell surface molecules CD80 and CD86 are

bound by CTLA4Ig, which prevents CD28 on T cells from binding and

T-cell activation. CTLA4Ig treatment was safe, well tolerated and did

not elicit an antibody response. It demonstrated effective inhibition of

DCs and macrophages (Kremer et al., 2003). Treatment of autoim-

mune disease with tailored chimeric antigen receptor-T cells (CAR-T)

is another emerging paradigm and is similar to tumour treatment in

that it relies on focused eradication of autoantigenic antibody-produc-

ing B cells, which are identified by their sensitivity to specific autoan-

tigens, without the risk of broad immunosuppression. Although CAR-

T cell therapy has demonstrated promise in the focused treatment of

autoimmune illnesses, its application is constrained by the real-world

difficulties posed by the heterogeneity and complexity of autoimmune

diseases like RA. In order to specifically target different types of auto-

reactive B cell subsets, Zhang et al. developed a specific and modified

approach that used universal anti-fluorescein isothiocyanate CAR-T

cells in combination with fluorescein isothiocyanate-labelled RA-

immunodominant peptides. The study highlighted the promising

potential of CAR T cell therapy against RA (Zhang, Wang, et al., 2021).

6.3 |MSC therapy

MSCs are multipotent stem cells having immunomodulatory, regener-

ative and tissue-protective properties that produce large amounts of

exosomes, which have been indicated for the transport of RNAs for

therapeutic delivery mechanisms (Yang et al., 2023). HAND2-AS1, a

long non-coding anti-sense RNA, is an established tumour suppressor

in cancers. Early studies have shown how these RNA fragments are

present in small quantities in the RA FLS. Upregulation of these same

long non-coding anti-sense RNAs in RA FLS in vitro not only inacti-

vated the proliferation, infiltration and migration of the synoviocytes

but also induced their apoptosis through the impairment of NF-κB

TCF p65. MSC-derived exosome-enclosed HAND2-AS1 when

incubated with RA-FLS suppressed growth and mobility and success-

fully halted the progression of RA (Su et al., 2021). MSCs have been

explored for therapeutic activity in autoimmunity for their immuno-

suppressive characteristics (Sardana et al., 2023). They have been

comprehended to migrate to inflammatory corners and cease the

proliferation of T and B cells (Luque-Campos et al., 2019). B7-H1 is a

co-stimulator found on the surface of activated T cells, B cells, mono-

cytes, and cancer cells. A study established that B7-H1 expressing

human gingiva-derived MSCs (GMSCs) show a stronger immunosup-

pressive potential than B7-H1-low GMSCs in CIA murine models

through interaction with STAT3 signalling pathway (Wu, Xiao,

et al., 2020). The positive effect of GMSCs on autoimmune disorders

was validated by a study showing restoration of the appropriate ratio

of Th-17 cells and upregulation of T-reg cells on GMSC induction in

uveitis-induced mice (Gao et al., 2023). Another study investigated

the transfer of MSC-derived mitochondria to CD4

T cells and con-

cluded that mRNA expression of T cell activation and T-reg cell devel-

opment were elevated, thus making the CD25

Foxp3

T-reg

population exploitable. This made possible the alleviation of tissue

damage in mice and reduced transplantation rejection. This concept

can be utilised in repairing RA-affected joints and preventing further

damage by enhancing the activation of T-reg cells (Court et al., 2020).

6.4 |Tolerogenic DC therapy

DCs are specialized APCs whose role was initially defined by their

ability to stimulate naive T cells and initiate successful T cell

responses. Serving as sentinels of the immune system, these cells link

innate immunity to acquired immunity, patrolling the body for anti-

gens and capturing them. Moreover, it is now understood that DC

play a key role in the development and preservation of peripheral T-

cell tolerance. Tolerogenic DCs induce immunological peripheral toler-

ance by several methods, including inhibiting T cell clonal proliferation

and induction of T cell anergy, deletion of T lymphocytes and induc-

tion of Tregs (Kiss et al., 2013). There are two types of Tregs: naturally

occurring T-reg cells that emerge in the thymus and adaptive T-reg

cells that are induced in the periphery (Haribhai et al., 2009; Hilkens &

Isaacs, 2013). Bianco et al. formerly proved that DCs treated with

immunosuppressive cytokines, as well as exosomes produced from

DCs, can inhibit the onset and severity of murine CIA. Indoleamine

2,3-dioxygenase (IDO) is a tryptophan-hydrolysing enzyme that is

essential for immunological modulation and maintenance of tolerance.

T cells can be inhibited by DCs expressing functioning IDO by deplet-

ing them of critical tryptophan and/or manufacturing toxins, as well as

by producing Treg cells. The purpose of this work was to look at the

immunosuppressive effects of bone marrow-derived DCs that had

been genetically engineered to express IDO, as well as exosomes

formed from IDO-positive DCs. Study findings reveal that IDO-

expressing DCs and DC-derived exosomes are immunosuppressive

and anti-inflammatory and that they can reverse established arthritis.

Exosomes from IDO-positive DCs may thus represent a potential

therapeutic for RA (Bianco et al., 2009). Kim et al. demonstrated that

16 CHATTERJEE ET AL.

periarticular introduction of exosomes purified from bone marrow-

derived DCs transduced ex-vivo with an adenovirus expressing viral

IL-10 or bone marrow-derived DCs treated with recombinant mice IL-

10 suppressed delayed-type hypersensitivity responses in contralat-

eral joints. Furthermore, systemic administration of IL-10-treated DC-

derived exosomes suppressed the onset of CIA model in mice and

reduced the severity of arthritis. These findings imply that immature

DCs can release exosomes that are important in the inhibition of

inflammatory and autoimmune responses. As a result, DC-derived

exosomes could be a potential cell-free therapeutic option for the

management of autoimmune disorders (Kim et al., 2005). A peptide

vaccine developed to induce the generation of tolerogenic DCs in an

ongoing inflammatory condition ameliorated joint destruction and

enhanced citrulline tolerance by upregulating T-reg and IL-10 popula-

tions (Chen et al., 2021). Exosomes secreted by DCs loaded with

MHC class II molecules effectively activated specific T cells. This strat-

egy could be manipulated to engage T-reg cells for the promotion of

self-tolerance (^

Ale ´

A ne Vincent-Schneider et al., 2002). This treat-

ment strategy is an effective targeted approach to the management of

the disease, and with enough clinical support, can be.

7|HERBAL INTERVENTIONS WITH

POTENTIAL ANTI-RHEUMATIC ACTIVITY

Recently, there has been an elevated interest in substances of natural

origin for exploration of anti-arthritic therapeutic activity, owing to

the accumulating evidence regarding the adverse events related

to modern medicine (Lee et al., 2012; Manan et al., 2020; Moon

et al., 2015). Common targets of traditional herbal medicinal com-

pounds against RA are Th cells, FLS, B cells, macrophages, DCs, miR-

NAs, angiogenesis pathways, osteoclasts and so on (Wang, Chen,

et al., 2021). Hence, herbal alternatives are being revisited for phar-

macological properties. In this section, we summarize 10 anti-inflam-

matory, anti-arthritic and anti-rheumatic herbs that have shown

intense potential to be developed into treatments against RA. The

same herbs and their major phytoconstituents have been summarized

in Figure 5. The in vitro and in vivo studies done on these 10 herbs

have been summarized in Tables 2and 3, respectively.

7.1 |Salix nigra Marshall

The bark of the willow tree (genus: Salix) is a sumptuous natural

source of invaluable bioactive compounds like phenolic glycosides, fla-

vonoids and polyphenols (Mahdi, 2010). Salicylic acid (derived from

salicin), one of the oldest medicinal compounds was discovered from

this tree, which went on to become one of the major classes of anti-

inflammatory, anti-rheumatic, antipyretic and analgesic drugs (Gligori

et al., 2020). Apart from that they also possess glycemia and pro-

thrombin-modulating aspects (Shara & Stohs, 2015). Overall, 322 com-

pounds are identified from leaf and bark extracts of the Salix herbs

including flavonoids (flavonols, flavones, flavanones, catechins,

procyanidins, chalcones, dihydro flavonols), phenolic glycosides,

organic acids, non-phenolic glycosides, sterols, terpenes, lignans, vola-

tiles and fatty acids (Wang et al., 2014). Phenolic compounds present

are mainly caffeoylhexoses and caffeoylquinic acids. Flavanols and

procyanidins include epicatechins and epigallocatechins. Flavonols

characterized are quercetin derivatives, kaempferol pentoside and iso-

rhamnetin (Piątczak et al., 2020). Methanolic extract of Salix nigra

exhibited strong antioxidant properties by scavenging free radicals of

nitric oxide and hydrogen peroxide and lowering lipid peroxidation in

the CIA model of rats. In vivo, studies proved that rats treated with

this preparation experienced a diminished arthritis score in terms of

reduction in erythema and paw volume. The extent of disease charac-

terized by cartilage injury, immune cell infiltration, joint damage and

synovial hyperplasia was reduced in rats treated with Salix extract, as

compared to control rats treated with CIA (vehicle only). Levels of

pro-inflammatory cytokines TNF-α, IL-1βand IL-6 were lowered to a

greater extent in CIA rats treated with methanolic Salix extract as

compared to CIA rats administered with known NSAID indomethacin

(Sharma et al., 2011). Willow extracts included in the diets of CFA-

induced rats improved levels of anti-inflammatory IL-10 and antioxi-

dants superoxide dismutase and glutathione. Consequently, histopath-

ological evidence showed that rheumatoid symptoms of oxidative

stress and abnormal inflammation were alleviated (Faid, 2021). There-

fore, plant extracts of the Salix genus offer a favourable possibility for

a treatment regimen for RA.

7.2 |Boswellia serrata Roxb.

The resin of Boswellia serrata (also called Frankincense) has been tradi-

tionally used to treat chronic inflammatory disorders. The gum of Bos-

wellia contains monoterpenes, diterpenes, triterpenes, tetracyclic

triterpenic acids and four major pentacyclic triterpenic acids such as

β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and

acetyl-11-keto-β-boswellic acid (Sharma et al., 2007; Siddiqui, 2011).

Essential oils derived from leaf extracts of this plant consist of

cymene, limonene, terpinolene, bornyl acetate, pinene, thujene, phel-

landrene and terpineol (Sharma et al., 2007; Sharma et al., 2009). The

gum extract of this plant shows immunomodulatory effects such as

inhibition of the complement system, NF-ĸB and MAPK pathways

(Goswami et al., 2018), pro-inflammatory cytokine IL-1, IL-2, IL-4, IL-6

and IFN-γproduction (Ammon, 2010; Eltahir et al., 2019). The gum

resin of the Boswellia plant reduces symptoms of CFA-induced RA

such as inflammation in Wistar rats. This extract consists of boswellic

acids that can suppress the production of pro-inflammatory cytokines,

along with possessing antipyretic and analgesic activities. RA symp-

toms like pain, swelling, and erythema arise mainly from inflammation

and immunological activation (Afsar et al., 2012). Boswellia extract has

shown a substantial attenuation of inflamed paw volume and arthritic

scores, as well as lowering of cartilage damage, synovial hyperproli-

feration, pannus and vascular infiltration that are characteristic fea-

tures of RA. This in vivo study went on to show weight gain after

arthritis-induced weight loss. However, this concoction failed to

CHATTERJEE ET AL.17

effectuate any changes in the TNF-αlevels in the rats' sera (Kumar

et al., 2019). A research study proved the anti-inflammatory property

of B. serrata extract by showing a reduction of cellular proliferation

and paw volume in rats immunized with an emulsion of complete

Freund's adjuvant and type II collagen (CIA model of arthritis). The

preparation of Boswellia extract also diminished the levels of articular

elastase and myeloperoxidase. These enzymes are responsible for

elastin protein degradation, neutrophil activity and synovial infiltration

in the joints. Additionally, the extracted mixture also inhibited lipid

oxidative damage of the cartilage, and most importantly, repressed

the generation of pro-inflammatory cytokines like IL-1β, IL-6, TNF-α,

IFN-γand PGE2, inferred from enzyme linked immunosorbent assay

analyses (Umar et al., 2014). Boswellia herbs can thus be promoted to

be considered as therapeutic alternatives for the treatment of RA.

7.3 |Curcuma longa L.

The classes of phytochemicals present in Curcuma rhizome extract are

composed of carbohydrates, proteins, starch, amino acids, steroids,

glycosides, flavonoids, alkaloids, tannins and saponins (Sawant & God-

ghate, 2013). The high performance liquid chromatography chromato-

gram of Curcuma longa rhizome extract contains peaks for caffeic acid

hexoside, curdione, coumaric acid, caffeic acid, sinapic acid, quercetin-

FIGURE 5 Representative herbs and their major phytoconstituents with potential activity against rheumatoid arthritis.

18 CHATTERJEE ET AL.

TABLE 2 In vitro studies of the medicinal herbs against rheumatoid arthritis (RA).

Herbs

Part of

plant used Study objective Cell lines used Result and inference Reference

Salix nigra Marshall Bark Evaluation of the anti-inflammatory effect

of salix extract

Primary human monocytes (CD14/CD36

positive peripheral mononuclear cells)

stimulated by LPS

•Inhibition of COX-2 mediated PGE2

release

•Steady decrease in release of LPS

induced IL-6, TNF-αand IL-1β

Fiebich and Chrubasik

(2004)

Boswellia serrata Roxb. Leaves Investigation of anti-inflammatory activity

of Boswellia leaf extract

Human red blood cells •Substantial stabilisation of Human

erythrocyte membranes indicating anti-

inflammatory activity comparable with

NSAIDs

Afsar et al. (2012)

Curcuma longa L. Rhizome Determination of anti-inflammatory

activity of turmeric extract

LPS induced RAW 264.7 •Suppressed cell proliferation.

•Downregulation of IFN-γ, IL-6, IL-13

and TNF-α

Lee et al. (2020)

Zingiber officinale

Roscoe

Rhizome Evaluation of the anti-inflammatory

efficacy

THP •Inhibition of TNF-α, IL-1 and IL-6

•Slight induction of production of anti-

inflammatory cytokines TGF-βand

IL-10

Mohammed et al.

(2019)

Piper longum L. Fruits Demonstration of anti-inflammatory

potential of Retrofractamide C, a major

phytocomponent extracted from Piper

longum

LPS-Induced J774A.1 cells •Suppression of nitric oxide and PGE2

generation

•Lowering of iNOS and COX2 enzyme

production

•Inhibition of IL-6 and IL-1βgene

expression

•Attenuation of phosphorylated ERK

and NF-κB, p65

Lim et al. (2020)

Pluchea lanceolata

(DC.) C.B.Clarke:

Leaves Evaluation of the immunosuppressive

properties

Peritonial murine macrophages opsonized

with heat killed Candida albicans

•Significant reduction in phagocytic

activity of macrophages treated with

Pluchea extract

Bhagwat et al. (2010)

Commiphora wightii

(Arn.) Bhandari

Exudate Determination of the effect of

guggulsterone on LPS induced

inflammation

Murine macrophage RAW 264.7 cell line •Guggulsterone inhibited mRNA

expression of TNF-αand iNOS

•Guggulsterone inhibited the

phosphorylation of IκB with dose-

dependency

Zhang et al. (2016)

Paederia foetida L. Leaves Investigation of anti-inflammatory

potential

Standard COX-1, COX-2 and LOX kits •72.23 ± 4.53% inhibition of COX-1

•82.84 ± 4.85% inhibition of COX-2,

which is significantly higher than

quercetin and comparable with

indomethacin

Kumar et al. (2015)

(Continues)

CHATTERJEE ET AL.19

3-D-galactoside, casuarinin, bisdemethoxycurcumin, curcuminol,

dimethoxycurcumin, isorhamnetin, valoneic acid bilactone, curcumin

and curcumin-O-glucuronide (Sabir et al., 2021). C. longa (turmeric) is

traditionally used for ages for its numerous activities. The main bioac-

tive component of C. longa (turmeric) rhizome, curcumin, which

imparts the yellow colour to turmeric, possesses anti-inflammatory,

antioxidant, anti-cancer and anti-arthritic properties, and has dis-

played a wide regulation of various cellular pathways and transcription

processes (Rapalli, Kaul, et al., 2020). Its anti-inflammatory activities

involve the modulation of a spectrum of cytokines, chemokines,

growth factors, adhesion components and enzymes such as COX-2.

These functions are possible by the effectuation of NF-κB, JAK–STAT

MAPK and other kinase pathways by curcumin, which also make it a

potent chemotherapeutic molecule (Goel et al., 2008; Sharma

et al., 2005). In a research study, the efficacy of curcumin and diclofe-

nac sodium were compared in treating RA, and curcumin resulted in

fewer adverse events as compared to the standard NSAID. Curcumin

proved to be a well-tolerated analgesic as compared to diclofenac,

along with bringing overall improvement in RA patients (Chandran &

Goel, 2012). There is evidence to prove that curcumin shows anti-

inflammatory effects by downregulating pro-inflammatory factors like

TNF-α, IL-1β, IL-6, 8 and 12. In a study, IL-6, IL-8 and MMP 1 and

3 production in IL-1βinduced RA FLS was restricted by the introduc-

tion of curcumin. This potent compound also curbed Th cell produc-

tion and enhanced T-reg cell differentiation during immune activation.

The only limitation associated with the use of this molecule is its low

bioavailability, and hence, nanoparticle-encapsulation was investi-

gated for this compound's better delivery at the site in question

(Waghule et al., 2020). Liposomal curcumin shows strong inhibition of

inflammatory responses and increased anti-inflammatory cytokine

production (Feng et al., 2017). Micellar encapsulation of curcumin has

also been explored for effective transport (Gou et al., 2011; Moham-

madian Haftcheshmeh & Momtazi-Borojeni, 2020). The enormous

potential of Curcuma plants makes them a strong prospect to be

developed into management options for the disease.

7.4 |Zingiber officinale Roscoe

The source of the popular edible rhizome, ginger, is the Zingiber offici-

nale plant. The Z. officinale plant contains anti-oxidant and anti-ar-

thritic potential, as suggested by in vitro and in-silico studies

(Murugesan et al., 2020). A study has shown that ginger extract can

bring anti-inflammatory impacts through inhibition of IL-1,6, nitric

oxide, PG (mainly PGE2) and leukotriene synthesis, thus, inhibiting

joint inflammation in streptococcal cell wall-induced arthritis in mice

(Funk et al., 2016). The active constituents identified were mainly

comprised of phenols (gingerols, paradols), sesquiterpenes (zingiber-

enes, zingiberols) and vitamins (thiamine, riboflavin, niacin, pyridoxine,

etc.) (Al-Nahain et al., 2014). Z. officinale juice mainly contains three

gingerols: 4-gingerol, 6-gingediol and 6-gingerol (Bekkouch

et al., 2022). The fresh ginger rhizome is comprised of phytoconstitu-

ents of two categories: volatile and non-volatile compounds. Volatile

TABLE 2 (Continued)

Herbs

Part of

plant used Study objective Cell lines used Result and inference Reference

Vitex negundo L. Seeds Determination of anti-inflammatory and

anti-osteoporotic properties

LPS stimulated RAW 264.7 macrophages

and rat osteoblast-like UMR106 cells

•Strong inhibition of nitric oxide

production through interference with

nitric oxide synthase protein

expression in LPS-stimulated

RAW264.7 cells comparable to

indomethacin

•11.4% inhibitory effect of osteoclastic

trate-resistant acid phosphatase

activity in UMR106 cells

Zheng, Zhang, et al.

(2014)

Ricinus communis L. Leaves Assessment of anti-inflammatory activities LPS stimulated RAW 264.7 macrophage

cell lines

•Reduction of free radicals (ROS) in LPS

stimulated cells, which will lead to

reduction in inflammation

Nemudzivhadi and

Masoko (2014)

Abbreviations: CD, cluster of differentiation; COX, cyclooxygenase; ENA, epithelial cell-derived neutrophil activating peptide; ERK, extracellular signal-regulated kinase; IL, interleukin; iNOS, inducible nitric oxide

synthase; LOX, lipoxygenase; LPS, lipopolysaccharide; MMP, metalloproteinases; MTT, 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide; NF-ĸB, nuclear factor kappa-light-chain-enhancer of

activated B cells; PG: prostaglandin; RA-FLS, rheumatoid arthritis fibroblast-like synoviocytes; RANTES, regulated upon activation, normal t cell expressed and presumably secreted; ROS, reactive oxygen

species; TNF, tumour necrosis factor.

20 CHATTERJEE ET AL.

TABLE 3 In vivo studies of medicinal herbs against rheumatoid arthritis (RA).

Herb species

Part of

plant used Study objective Animal model Results Reference

Salix nigra Marshall Leaves Exploration of treatment effect of

willow leaves in rheumatoid arthritis

Sprague Dawely Rats with Collagen

Induced Arthritis (administration of

collagen emulsified with CFA)

•Increased antioxidant levels of

glutathione and superoxide

dismutase, thus reducing oxidative

stress

•Decreased levels of pro-

inflammatory TNF-α, and increased

anti-inflammatory IL-10 levels

•Thinning of inflamed synovium,

reduced inflammatory lesions on

joint

Faid (2021)

Boswellia serrata

Roxb.

Exudate (gum

resin extract)

Evaluation of anti-inflammatory

property

Adult female Lewis rats with CFA

induced arthritis

•Significant reduction of rat paw

oedema

•Decreased arthritic score

•Decreased IL-17 levels

•Increased anti-oxidant capacity of

blood

St-Pierre et al. (2018)

Curcuma longa L. Rhizome Evaluation of antiarthritic efficiency of

turmeric extract

Adjuvant induced arthritis model in

Male Wistar Rats

•Reduced joint swelling by 41.3%

•Diminished serum levels of IL-17

•Reduced synovial membrane and

leukocyte infiltration

Brad

unaitėet al. (2020)

Zingiber officinale

Roscoe

Rhizome Determination of anti-inflammatory

efficacy of ginger extract

CIA model in Female Wistar albino

rats

•Reduced mean arthritis scores

•Lowered serum levels of IL-6, IL-17

and TNF-α

•Downregulated NF-κB and COX-2

levels

•Decreased inflammatory

infiltration, synovial hyperplasia

•Improvement in cartilage and bone

destruction

Öz et al. (2021)

Piper longum L. Fruit Investigation of rate of alteration of

RA progression by Piperlongumine

CIA induced Male DBA/1 mice •Piperlongumine interfered with

inflammatory cell infiltration into

synovium, cartilage damage, pro-

inflammatory cytokine production,

migration and invasion of RA FLS.

•Piperlongumine upregulated levels

of Myeloid derived suppressor cells

Sun et al. (2015)

(Continues)

CHATTERJEE ET AL.21

TABLE 3 (Continued)

Herb species

Part of

plant used Study objective Animal model Results Reference

Pluchea lanceolata

(DC.) C.B.Clarke

Whole plant Exploration of the anti-inflammatory

and anti-arthritic activities of four

flavonoids

Adult albino rats of either sex •The bio-actives showed anti-

inflammatory and anti-arthritic

effects against pedal inflammation

and granuloma formation.

•The concoction showed less

efficacy than betamethasone but

possessed the advantage of

manifesting no adverse gastric

lesions as in case of the steroid

Shankar Pandey and Trigunayat

(2018)

Commiphora wightii

(Arn.) Bhandari

Exudate (gum

resin)

Investigation of anti-inflammatory

effects of aqueous extract of gum

resin

Carrageenan induced rat hind paw

oedema

•Decrease in rat hind paw oedema

•Significant reduction of

inflammatory biomarkers

Shekhawat et al. (2021)

Paederia foetida L. Whole plant Evaluation of anti-inflammatory

property

Carrageenan induced paw oedema

model in Wistar Albino rats

•The butanolic extract showed the

best dose-dependent decrease in

oedema of up to 79.2%

Bandiya et al. (2022)

Vitex negundo L. Seeds Estimation of therapeutic effects CFA induced arthritis in Male Wistar

rats

•Subsidence of rat paw oedema,

synovial layer hyperproliferation

and inflammatory cell infiltration,

chronic inflammation, pannus

build-up and bone resorption

•Downregulation of TNF-αand IL-

1β, IL-6; upregulation of IL-10

•Reversal of weight loss as observed

after induction of arthritis.

•Marked reduction of COX-2

and 5-LOX

Zheng, Zhang, et al. (2014),

Zheng, Zhao, et al. (2014)

Ricinus communis L. Leaves Evaluation of anti-arthritic activity CFA induced arthritis in Wistar rats •Hydroalcoholic extract of Ricinus

root showed significant decrease in

arthritic scores

•Reduction of paw oedema

•Improvement in body weight

Hussain et al. (2021)

Abbreviations: CFA, complete Freund's adjuvant; COX, cyclooxygenase; DCM, dichloromethane; GSH, glutathione; IFN, interferon; IL, interleukin; LOX, lipoxygenase; PG, prostaglandin; RA-FLS, rheumatoid

arthritis fibroblast-like synoviocytes; SOD, superoxide dismutase; TBARs, thiobarbituric acid reactive substances.

22 CHATTERJEE ET AL.

compounds consist of sesquiterpene hydrocarbons, which are mainly

zingiberene, curcumene and farnesene (Yousfi et al., 2021), which

contribute to the characteristic gingery taste and odour. Non-volatile

compounds are comprised of gingerols, shogaols, paradols and zinger-

one, which are responsible for the hot sensation on ingestion of the

rhizome. They also contain vitamins and enzymes named zingibain

(Gupta & Sharma, 2014). The dichloromethane (DCM) extract of dried

pulverised ginger was experimentally detected as containing various

gingerols, some oils, terpenes and polar moieties. These compounds

were collectively found to ameliorate the synthesis of PGE2 in vitro,

out of which gingerols and their variations were witnessed to be key

contributors to this anti-PG effect, with complimentary effects by the

non-gingerols. Further in vivo studies compared a phenolic prepara-

tion versus a similar crude DCM extract of the gingerol components

administered intra-peritoneally substantially deferring synovial inflam-

mation and bone damage in streptococcal cell wall-induced arthritis

model in mice, with the DCM extract showing better efficacy (Funk

et al., 2009). Another in vivo study suggested the anti-inflammatory

activity of zingiber by reducing rat paw oedema in arthritic rats (Bek-

kouch et al., 2022). Therefore, it is evident that plants of the genus

Zingiber carry the promise of an established solution for

the management of RA.

7.5 |Piper longum L.

Plants belonging to the genus Piper have famously been reported to

be of pharmacological significance, with Piper longum being one of the

most important species in the genus. P. longum, also identified as long

pepper, is mentioned in ancient literature to be possessing medicinal

properties (Khandhar et al., 2010). The P. longum plant contains bioac-

tive alkaloids such as piperine, methylpiperine, iperonaline, piperet-

tine, asarinine, pellitorine, piperundecalidine, piperlongumine,

piperlonguminine, piperazine, methyl-3,4,5-trimehoxycinnamate and

many more. Other than that, they also contain lignans, esters and vol-

atile oils (Khandhar et al., 2010; Khushbu et al., 2011). Piperine is the

major active component of the Piper family, which can be extracted

from P. longum,orPiper nigrum. Piperine acts as a potent bio-enhancer

to many other bioactives. A systematic review of different

publications on P. longum reported that it exhibits analgesic, anti-

inflammatory, and anti-arthritic behaviour among a vast list of activi-

ties (Yadav et al., 2020). Piperlongumine weakened the pathological

damage in the form of inflammatory cell penetration as well as carti-

laginous damage in the CIA mice model through the attenuation of

serum Ig levels and cytokine production of TNF-α, IL-1β, IL-23 and IL-

17 in the mice sera. The investigation suggested that the Piperlongu-

mine substantially decreased Th-17 cells in the lymph nodes, along

with a sharp rise in myeloid-derived suppressor cells (MDSCs) that are

capable of suppressing T-cell mediated inflammatory responses. How-

ever, it did not affect the T-reg cells. Piperlongumine was also able to

suppress the migratory nature of the human RA-FLS (Sun et al., 2015).

Another study by Xiao et al. (2016) demonstrated the ability of piper-

longumine to ameliorate LPS-induced DC maturation, reactive oxygen

species production by DCs and activation of p38, JNK, NF-ĸB and

PI3K/Akt signalling pathways. A dose between 200 and 400 mg/kg of

aqueous extract of P. longum seeds shows an effective reduction in

rat paw volume in CFA-induced arthritic rats (Yende, 2010). In Com-

plete Freund's Adjuvant-induced arthritis in mice, solid lipid nanoparti-

cles encapsulating piperine also brought a greater reduction in

inflamed paw volume as compared to a suspension of chloroquine as

an anti-rheumatic standard. The researchers suggested the reason

was that topical and oral piperine localised more effectively at the tar-

get site. These piperine preparations also demonstrated marked inhi-

bition of bone disintegration, suppression of TNF-αrelease from

macrophages, angiogenesis, joint infiltration and distortion (Bhalekar

et al., 2017). The anti-inflammatory properties of the Piper plant offer

immense capacity to be expanded to a course of medication for RA.

7.6 |Pluchea lanceolata (DC.) C.B.Clarke

The plant Pluchea lanceolata belongs to the family Asteraceae and is

known to possess anti-inflammatory, analgesic, anti-ulcer, anti-micro-

bial, anti-nociceptive, antipyretic, anti-rheumatic and neuroprotective

characteristics (Kamel & Ahemd, 2013; Srivastava & Shanker, 2012).

The leaves of this plant were discovered to be abundant in bioactive

metabolites such as flavonoids, phenolic compounds, alkaloids, terpe-

noids, sterols, and so forth (Sharma & Goyal, 2011). The major com-

pounds found in the pulverised powder of the stem of this plant

found through gas chromatography–mass spectrometry–MS analysis

are quercetin, hesperetin-7-rutinoside, taxifolin-3-arabinoside, formo-

nonetin-7-O-glucoside, isorhamnetin, decanoic acid, octadecanoic

acid, cyclopentadecanone, stearic acid, heptadecane, tetracosane,

docosane and hexadecenoic acid (Gour et al., 2012; Kamel &

Ahemd, 2013). The ethanolic extract of the leaves of P. lanceolata

exhibited significant anti-inflammatory behaviour, which was further

fractionated into a hexane extract that showed optimum anti-inflam-

matory suppression of carrageenin-triggered oedema in the rat paw,

owing to psi-taraxasterol acetate acting as the active ingredient

(Garg & Manisha, 2020). The leaf extract of this herb showed inhibi-

tion of both cellular and humoral antibody responses through the

downregulation of pro-inflammatory cytokines and effective suppres-

sion of CD4

and CD8

T cells (Bhagwat et al., 2010). Another study

similarly proved the anti-inflammatory and anti-arthritic activity of fla-

vonoids present in P. lanceolata extract using albino rats. Although its

activity was not as strong as betamethasone, there was a notable dif-

ference in the incidence of gastric lesions and haemorrhagic ulcers

which was 50% higher in the case of established anti-inflammatory

corticosteroid betamethasone (Shankar Pandey & Trigunayat, 2018).

The Pluchea plant possesses the properties required for the ameliora-

tion of the disease conditions of RA.

7.7 |Commiphora wightii (Arn.) Bhandari

Commiphora wightii has been traditionally utilised for its famously

known effects against arthritis, inflammation, gout, rheumatism and

metabolic disorders (Sarup et al., 2015). The white exudate from the

CHATTERJEE ET AL.23

Commiphora plant contains a concoction of volatile oils containing ter-

penes and terpenoids, sterols, sterones, steroids, lignans, flavonoids

and flavanones. The major volatile oils are myrecene, dimyrecene,

polymyrecene and resins or guggulsterols (Rani & Mishra, 2013; Sarup

et al., 2015). Guggulsterone (4,17(20)-pregnadiene-3,16-dione) is

named after the common name of the plant, guggul (Kunnumakkara

et al., 2018). Z-guggulsterone and E-guggulsterone, predominant ste-

roids present in this herb, exhibited potent inhibition of nitric oxide

production in LPS-induced murine macrophage cell line J774.1 (IC

21.1 and 42.3 mM, respectively) (Meselhy, 2003). Cis and trans iso-

mers of this compound reportedly inhibited the production of chemo-

kines regulated upon activation, normal t cell expressed and

presumably secreted and epithelial cell-derived neutrophil activating

peptide-78 in IL-1βtreated FLS, allegedly by some interference with

the farnesoid X receptor (Bile acid) signalling pathway. 3-(4,5-

Dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay of this

setup revealed that guggulsterone also curtailed the hyperprolifera-

tion seen in the IL-1βtreated FLS by 101.3 ± 4.2% and 98.3 ± 3.7%,

respectively. IL-1β-induced MMP secretion by FLS was also sup-

pressed by treatment with this potent natural compound. It is known

that chemokines are secreted by FLS and macrophages through acti-

vation of the NF-κB cascade. Moreover, IL-1βwas proved to increase

the association of TCF NF-κB with its corresponding consensus

sequence. Cis and trans guggulsterone demonstrated inhibition of

MMP production through interference with the NF-κB route, along

with significantly decreasing IκBαdegradation and consequently muf-

fled NF-κB activation (Lee, Lee, Noh, et al., 2008). Electrophoretic

mobility shift assay established that guggulsterone abolished RANKL

mediated NF-κB induction in a dose-dependent manner with optimum

inhibition at 50 μmol/L concentration. Pretreatment of cells with gug-

gulsterone restricted the phosphorylation of IκBα(Inhibitor of κB-α),

which is needed for NF-κB activation without interfering with the

amount of IKKαor IKKβ. Osteoclast differentiation was consequently

tapered (more than 90%) in RAW 264.7 cells cultured in the presence

of a low concentration of 5 μmol/L of this active compound (Ichi-

kawa & Aggarwal, 2006). Plants belonging to the genus Commiphora

as a whole possess anti-inflammatory properties (Dinku et al., 2022).

This plant and its phytoconstituents can thus emerge as a prospective

treatment option for RA.

7.8 |Paederia foetida L.

This plant belonging to the Rubiaceae family has been known for its

anti-inflammatory properties since pre-historic times and was even

used for the treatment of rheumatic diseases, being endowed with

principal bio-actives like iridoid glycosides, flavonoid glycosides, phe-

nolic derivatives, anthraquinones, triterpenoids, phytosterols, essential

oils, sterols and galacturonic acids (Dutta et al., 2023).

Essential medicinal extracts are obtained from multiple parts of this

invaluable plant, such as diuretic functions from a decoction of the

leaves, emetics from roots, dental analgesics from fruits and leuko-

derma suppressors from the seeds, to name a few. A carefully

prepared leaf extract demonstrated a higher dose-dependent inhibi-

tory effect on cotton pellet granuloma formation in Charles Foster

albino rats in comparison to phenylbutazone, an established NSAID.

There also exist reports of methanolic and hexane extracts of this

herb offering an anti-nociceptive effect measured by a reduction in

writhing in rats administered with acetic acid (Wang et al., 2014). A

study by Das et al. (2012) showed that Paederia leaf extract in ethanol

had an anti-nociceptive effect by demonstrating an increase in tail

flicking time, and an anti-inflammatory effect based on rat paw

oedema volume reduction. A 100 mg/kg body weight oral administra-

tion of desiccated methanolic extract of Paederia foetida leaves dimin-

ished paw oedema induced by injecting turpentine oil in Swiss albino

rats by 45%. This same dose also exhibited substantial inhibition of

pro-inflammatory cytokines IL-2, IL-1βand TNF-αin rats with CFA-

induced arthritis. Inflammation was induced by using alternative com-

pounds like arachidonic acid and PGE2, oedema being considerably

restricted in all these inflammatory models by the Paederia-derived

preparation. Additionally, neutrophil infiltration was also hindered

proportionately with dose by treating the arthritis-ridden rats with the

extract (Kumar et al., 2015). As a result, it can be stated that the com-

ponents of this herb can be certainly incorporated into management

regimens for RA.

7.9 |Vitex negundo L.

Traditionally known for its medicinal properties, the Vitex negundo

herb has been reported to possess anti-arthritic, anti-inflammatory

and anti-rheumatic potency (Vishwanathan & Basavaraju, 2010).

Extracts from various parts of the plant contain flavonoids, lignans,

terpenoids, steroids and additional compounds like coumarins and

acids (Zheng et al., 2015). In male Wistar rats injected with Complete

Freund's Adjuvant, ethanolic extract (340 and 85 mg/kg) of the pul-

verised seeds of this plant brought a reduction of oedema in the rat

paws with an impact comparable with the strong drug methotrexate.

Moreover, the time taken to regain weight was lesser in CFA-treated

rats administered with Vitex extract as compared to CFA-treated rats

not administered with any extract or drug. The group of adjuvant-

induced arthritic rats treated with Vitex seed extract witnessed a

sharp improvement in arthritic condition in terms of reduction in

synovial inflammatory infiltration and synovial layer hyper-prolifera-

tion with hindrance in joint destruction. Evidence suggests that this

extract also facilitated resistance to inflammation, pannus generation,

bone damage, downregulation of pro-inflammatory cytokines, upregu-

lation of anti-inflammatory cytokines and a stark reduction in COX-2

and 5-lipoxygenase quantities in the peripheral blood mononuclear

cells (Zheng, Zhao, et al., 2014). Zheng et al. fractioned four lignans

from this extract called vitexdoin F, vitexdoin G, vitexdoin H and

vitexdoin I. One of these compounds, vitexdoin F, demonstrated inhi-

bition against nitric oxide generation in RAW264.7 macrophage cell

lines stimulated with LPS through interference with inducible nitric

oxide synthase enzyme with efficacy comparable with indomethacin,

offering potential inhibitory effect against bone resorption. They also

24 CHATTERJEE ET AL.

showed anti-osteoporotic activity in LPS-stimulated UMR106 osteo-

blastic cells. Vitexdoin H, clearly showed inhibition of osteoclastic tar-

trate-resistant acid phosphatase up to 11.4%, hinting at anti-RA

activity of V. negundo seeds. Thus, these substances offer positive

potential against RA (Zheng, Zhang, et al., 2014). It can be conclusively

suggested that the constituents of this plant can be processed and

developed into a mode of treatment for this autoimmune disease.

7.10 |Ricinus communis L.

Commonly known as the castor plant, Ricinus communis is of great

pharmacological value. The roots of this plant are known for its anti-

rheumatic, anti-nociceptive, immunomodulatory, anti-inflammatory,

wound healing and antioxidant properties (Jena & Gupta, 2012). Anal-

ysis of the raw methanolic extract of the root resulted in the detection

of compounds such as alkaloids, saponins, flavonoids, terpenoids, car-

bohydrates and various proteins. Gas chromatography–mass spec-

trometry analysis of Ricinus root extract revealed the presence of

major phytocompounds such as hexadecanoic acid (77.8%), 2-meth-

oxy-4-vinylphenol ethenone (28.4%), sucrose (12.6%) and heptatria-

cotanol (10.5%) among a vast variety of constituents (Pandey &

Tiwari, 2021). Hydroalcoholic extract of the leaves of this plant

(500 mg/kg body weight) reversed weight loss in CFA-induced

arthritic male Wistar rats, significantly attenuated inflammation in

their paws, reduced inflamed thymic and spleen mass, reduced levels

of inflammatory biomarkers such as C-reactive protein and RF as well

as IL-6, IL-17a, IL-1βexpression, upregulated INF-γ, IL-4 quantity,

downregulated RANKL mRNA generation and led to an overall decre-

ment in the arthritic score calibrated by the research group. Histo-

pathological studies revealed that this extract of R. communis was able

to counteract synovial inflammatory infiltration, bone resorption and

pannus build-up. Radiological data suggested that the plant also ame-

liorated joint space obstruction, ankylosis, tissue swelling and osteoly-

sis (Hussain et al., 2021). So, this herb holds substantial potential in

alleviating the symptoms of RA.

8|CONCLUSION AND FUTURE

PERSPECTIVES

This review expands on the risk factors that can potentially trigger the

onset of RA. These triggers can be of genetic, environmental or micro-

bial nature. They can also be dependent on the gender and lifestyle of

the individual. The sequential events of the pathophysiological pro-

gression of the disease are multifaceted. The first sign of this disease

is the break of immunological tolerance due to the above-mentioned

risk factors. This is followed by auto-antibody generation and aggre-

gation of antibody–antigen immune complexes that activate Fcγnoci-

ceptive receptors (on the surface of immune cells) that are highly

specific for IgG protein. This leads to a cascade of inflammatory

responses involving activation of immune cells such as neutrophils,

macrophages and mast cells, and overproduction of pro-inflammatory

cytokines. These cytokines act as messengers of inflammation and

trigger FLS, osteoclast and chondrocytes. The FLS in the synovium

begin to hyper-proliferate due to the upregulation of the cellular sig-

nalling pathways such as the JAK–STAT, MAPK/ERK, VEGF and

mTOR pathways. Consequently, the chondrocytes degrade the carti-

lage, the osteoclasts perform resorption of the bone tissue and the

ECM begins to disintegrate. As a result, there is pain and inflammation

in the joints, leading to loss of joint functionality and disabilities. The

current medications for this chronic condition include DMARDs,

NSAIDs, corticosteroids and biological drugs. When these strategies

fail, patients undergo surgical procedures such as arthroplasty or joint

replacement to restore the functionality of the joint. In this review,

we have highlighted the adverse events that follow the usage of these

therapeutic approaches. Due to these shortcomings, the risk–benefit

ratio of these lines of treatment is depreciating and the scientific com-

munity is turning its attention towards safer alternatives. Compounds

of natural origin have had leverage in the discovery of new drug enti-

ties and have remained pivotal participants of ancient therapy systems

(Sam, 2019). Although it is already established that medicinal herbs

have significant therapeutic potential against inflammatory conditions

like RA (Amalraj & Gopi, 2021), herbal medications are yet to be con-

sidered as a preferred treatment option. This review aims to empha-

size the immense potential of therapeutic herbs in the realm of the

medical world and their superiority in terms of lowered side effects as

compared to conventional treatment profiles. In-depth standardized

analytical procedures, molecular identification, safety and efficacy

evaluation parameters are required to validate the authenticity and

activities of these compounds. Thus, there is immense potential for

natural compounds to be introduced in the healthcare realm. Only

with strong scientific techniques can these herbs penetrate the world

of modern medicine, and that looks very feasible in today's scenario.

AUTHOR CONTRIBUTIONS

Amrita Chatterjee: Conceptualization; data curation; formal analysis;

visualization; writing –original draft; writing –review and editing.

Monisha Jayaprakasan: Conceptualization; data curation; formal anal-

ysis; visualization; writing –original draft; writing –review and editing.

Anirban Kr Chakrabarty: Conceptualization; data curation; formal

analysis; investigation; methodology; visualization; writing –original

draft; writing –review and editing. Naga Rajiv Lakkaniga: Formal anal-

ysis; funding acquisition; resources; software; supervision; validation;

writing –review and editing. Bibhuti Nath Bhatt: Data curation;

methodology; writing –review and editing. Dipankar Banerjee: Super-

vision; writing –review and editing. Avinash Narwaria: Supervision;

writing –review and editing. Chandra Kant Katiyar:

Supervision; writing –review and editing. Sunil Kumar Dubey: Con-

ceptualization; data curation; formal analysis; investigation; project

administration; resources; supervision; validation; visualization;

writing –review and editing.

ACKNOWLEDGEMENTS

The authors acknowledge R&D Healthcare Division, Emami Ltd., Kol-

kata, West Bengal, India. The authors gratefully acknowledge that this

CHATTERJEE ET AL.25

work is partially supported by NRL's Science and Engineering

Research Board SRG/2022/000091. All the authors are grateful for

the support.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflict of interest.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were cre-

ated or analyzed in this study.

ORCID

Amrita Chatterjee https://orcid.org/0009-0009-8635-2464

Monisha Jayaprakasan https://orcid.org/0009-0003-2453-9609

Anirban Kr Chakrabarty https://orcid.org/0000-0001-7165-7366

Naga Rajiv Lakkaniga https://orcid.org/0000-0001-8370-2224

Dipankar Banerjee https://orcid.org/0000-0002-6276-6816

Avinash Narwaria https://orcid.org/0009-0007-7137-1190

Sunil Kumar Dubey https://orcid.org/0000-0002-7554-3232

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Sep 2023
ACTA BIOCHIM POL

Mutation in the VEGF gene disturbs the production of chondrocytes and angiogenesis which are essential for cartilage health. Cytokines and chemokines produced by auto-activation of B-cells degrade cartilage. Bruton's Tyrosine Kinase (BTK) plays a crucial role in the activation of these B-cells. VEGF has a central part in angiogenesis, in the recruitment of endothelial cells, and is involved in mechanisms that result in tumour formation. The objective of this research is to investigate the potential role of VEGF polymorphism in the development of Rheumatoid Arthritis (RA) and the screening of potential natural, synthetic BTK inhibitor compounds as possible in-silico chemotherapeutic agents to control auto-activation of B-cells and cartilage degrading cytokines. In this study, it had been shown that allele A frequency was significantly higher than that of allele C in RA-positive patients as compared to controls. Hence it depicts that allele A of VEGF (rs699947) can increase the risk of RA while allele C has a protective role. The phytochemicals which showed maximum binding affinity at the inhibitory site of BTK include beta boswellic acid, tanshinone, and baicalin. These phytochemicals as BTK inhibitor give insights to use them as anti-arthritic compounds by nanoparticle drug delivery mechanism.

Decoding the Microbiome's Influence on Rheumatoid Arthritis

Article

Full-text available

Aug 2023

The aim is better to understand and critically explore and present the available data from observational studies on the pathogenetic role of the microbiome in the development of rheumatoid arthritis (RA). The electronic databases PubMed, Scopus, and Web of Science were screened for the relevant literature published in the last ten years. The primary outcomes investigated included the influence of the gut microbiome on the pathogenesis and development of rheumatoid arthritis, exploring the changes in microbiota diversity and relative abundance of microbial taxa in individuals with RA and healthy controls (HCs). The risk of bias in the included literature was assessed using the GRADE criteria. Ten observational studies were identified and included in the qualitative assessment. A total of 647 individuals with RA were represented in the literature, in addition to 16 individuals with psoriatic arthritis (PsA) and 247 HCs. The biospecimens comprised fecal samples across all the included literature, with 16S rDNA sequencing representing the primary method of biological analyses. Significant differences were observed in the RA microbiome compared to that of HCs: a decrease in Faecalibacterium, Fusicatenibacter, Enterococcus, and Megamonas and increases in Eggerthellales, Collinsella, Prevotella copri, Klebsiella, Escherichia, Eisenbergiella, and Flavobacterium. There are significant alterations in the microbiome of individuals with RA compared to HCs. This includes an increase in Prevotella copri and Lactobacillus and reductions in Collinsella. Collectively, these alterations are proposed to induce inflammatory responses and degrade the integrity of the intestinal barrier; however, further studies are needed to confirm this relationship.

Anti-Inflammatory Study and Phytochemical Characterization of Zingiber officinale Roscoe and Citrus limon L. Juices and Their Formulation

Article

Full-text available

Jul 2023

Zingiber officinale and Citrus limon, well known as ginger and lemon, are two vegetals widely used in traditional medicine and the culinary field. The juices of the two vegetals were evaluated based on their inflammation, both in vivo and in vitro. High-performance liquid chromatography (HPLC) was used to characterize different juices from Zingiber of ficinale Roscoe and Citrus limon. After the application of the HPLC method, different compounds were identified, such as 6-gingerol and 6-gingediol from the ginger juice and isorhamnetin and hesperidin from the lemon juice. In addition, the two juices and their formulation were assessed for their anti-inflammatory activity, in vitro by utilizing the BSA denaturation test, in vivo using the carrageenan-induced inflammation test, and the vascular permeability test. Important and statistically significant anti-inflammatory activities were observed for all juices, especially the formulation. The results of our work showed clearly that the Zingiber officinale and Citrus limon juices protect in vivo the development of the rat paw edema, especially the formulation F composed of the Zingiber officinale and Citrus limon juices, which shows an anti-inflammatory activity equal to −35.95% and −44.05% using 10 and 20 mg/kg of the dose, respectively. Our work also showed that the formulation was the most effective tested extract since it inhibits the vascular permeability by −37% and −44% at the doses of 200 and 400 mg/kg, respectively, and in vitro via the inhibition of the denaturation of BSA by giving a synergetic effect with the highest IC 50 equal to 684.61 ± 7.62 μg/mL corresponding to the formulation F. This work aims to develop nutraceutical preparations in the future and furnishes the support for a new investigation into the activities of the various compounds found in Zingiber officinale Roscoe and Citrus limon.

VEGF signaling: Role in angiogenesis and beyond

Article

Jan 2024
BBA-REV CANCER

1,25(OH)2D3 and Its Analogue Calcipotriol Inhibit the Migration of Human Synovial and Mesenchymal Stromal Cells in a Wound Healing Model – a Comparison with Glucocorticoids

Article

Aug 2023
J STEROID BIOCHEM

Vitamin D analogue calcipotriol is currently used in the local treatment of psoriasis. However, it also has antiproliferative and anti-inflammatory effects in the cells of the joint - suggesting a possible benefit in local treatment of arthritis. In this study, calcipotriol was studied in different in vitro methods to find out its effect on synovial and mesenchymal stromal cells. Primary human cell lines of osteoarthritis or rheumatoid arthritis patients (five mesenchymal stromal cells, MSC, and four synovial stromal cells, SSC) were cultured to study migration and proliferation of the cells in a wound healing model. The media was supplemented with calcipotriol, 1,25(OH)2D3, dexamethasone, betamethasone, methylprednisolone or control solution in 1 nM-100 nM concentrations. To see possible toxic effects of calcipotriol, concentrations up to 10µM in SSCs and MSCs were studied in apoptosis and necrosis assays in four cell lines. Calcipotriol and 1,25(OH)2D3, as well as the three glucocorticoids, reduced the migration of both SSCs and MSCs. In SSCs, the effect of calcipotriol and 1,25(OH)2D3 was at least as effective as with glucocorticoids, while with MSCs, the glucocorticoids were stronger inhibitors of migration. The antimigratory of calcipotriol and 1,25(OH)2D3 was consistently maintained in 10µM and 1µM. Calcipotriol was not toxic to MSCs and SSCs up to concentrations of 10µM. Calcipotriol, as well as 1,25(OH)2D3, exerts antimigratory and antiproliferative effects on human SSCs and MSCs of the joint. These effects are not caused by apoptosis or necrosis. Both calcipotriol and 1,25(OH)2D3 have similar effects as glucocorticoids without apparent toxicity, suggesting that calcipotriol might be an eligible candidate to the local treatment of arthritis with a broad therapeutic window.

Comprehensive insights into rheumatoid arthritis: Pathophysiology, current therapies and herbal alternatives for effective disease management

Abstract

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