Role of Nutrition in Rheumatoid arthritis & How

different Nutrients affect Nutritional status

Review Article
Submitted by:
Supervised by:
Subject Page no.
Abstract ……………………………………………………… 1
Introduction ……………………………………………………… 2
Pathogenesis of ………………………………………………………. 2
rheumatoid arthritis
Triggering stage ………………………………………………………... 3
Maturation stage ……………………………………………………….. 4
Targeting stage ……………………………………………………….. 4
Fulminant stage ……………………………………………………….. 6
Hyperplastic synovium ……………………………………………………….. 6
Cartilage damage ……………………………………………………….. 6
Bone erosion ……………………………………………………….. 6
Systemic consequences ……………………………………………………… 6
Signs and symptoms of ……………………………………………………… 7
rheumatoid arthritis
Diagnosis ………………………………………………………. 8
Imaging ………………………………………………………. 8
Physical examination ……………………………………………………….. 9
Treatment ……………………………………………………….. 9
Managing rheumatoid ……………………………………………………….. 9
arthritis with dietary
interventions
Weight loss ………………………………………………………. 9
vegan diet ………………………………………………………. 10
Mediterranean diet ……………………………………………………….. 10
Elemental diet ……………………………………………………….. 11
Elimination diet ………………………………………………………. 12
Essential fatty acids ………………………………………………………. 12
Green tea ………………………………………………………. 13
Probiotics ……………………………………………………….. 13
Spices ………………………………………………………… 13
Conclusion ………………………………………………………… 14
References …………………………………………………………. 15
Abstract

clinical nutrition has been playing an important role in managing a

number of diseases recently. Self-help through means of dietary
interventions can help in treatment of many serious disorders including
rheumatoid arthritis (RA)
Rheumatoid arthritis (RA) is considered the most common type of
autoimmune arthritis causes significant morbidity and
mortality. It is a chronic systemic, autoimmune disease with genetic and
environmental factor. Its hallmark feature is a persistent symmetric
polyarthritis (synovitis) that affects the hands and feet and can affect any
joint lined by a synovial membrane. it can cause pain and swelling in the
small joints of the hand and feet.
The goal of treatment of RA is to stop joint pain and swelling and prevent
joint damage.
fortunately, it's found that Early treatment give better long-term results.
recently, a large number of studies proved that diet has a central role in
disease progression.
nutrients which have anti-inflammatory and antioxidant properties such
as polyunsaturated fatty acids can play a protective role for RA
development, while others can have a harmful effect such as red meat and
salt.
Some dietary patterns and supplements can have protective effect such as
the Mediterranean Diet (MD), vitamin D and probiotics. So, it could be a
possible future adjunctive therapy beside the standard RA treatment.
Therefore, a healthy diet and lifestyle have a very important role in RA
treatment which must be considered in every RA patient's plan of treatment
Aim of work
The aim of this review is to address the role of nutrition in managing and
preventing chronic diseases such as rheumatoid arthritis and its
complications.
Introduction
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory autoimmune
disorder affecting approximately 1% of the world population. The disease
severely impacts quality of life and causes significant morbidity and mortality.
With the rapidly expanding population with RA, the disease has cost the
society a lot of economic burden. (Khanna et al., 2017)
Rheumatoid arthritis (RA) is characterized by a systemic immune-
inflammatory response leading to Joint pain and fatigue associated with the
inflammatory process, deformities that hinder the performance of
daily activities result in work disability, early retirement leading to economic
losses (Zarpellon et al., 2022)
One of the causes of increased mortality in these patients is the accelerated
atherosclerosis by the chronic inflammatory process which lead to many
cardiovascular problems. It is estimated that a RA patient is 1.5 to 2 times more
likely to develop myocardial infarction than the general people. This risk is
compared to that of a patient with diabetes mellitus type 2 and can be increased
by the other risk factors such as obesity (Pereira et al., 2012).
RA mainly attacks the joints. It has the ability to attack many joints at once.
It commonly affects joints in the hands, wrists, and knees. In a joint affected
with RA, the lining of the joint becomes inflamed leading to damage in joint
tissue. This tissue damage can cause chronic pain, lack of balance and
deformity (misshapenness) ("Rheumatoid Arthritis (RA) | Arthritis | CDC",
2022).

RA can also affect other tissues throughout the body and may affect several
organs, such as the lungs, eyes, and blood vessels.

Pathogenesis of RA
RA is divided into two subtypes according to the presence or absence of
anti-citrullinated protein antibodies (ACPAs). Citrullination is catalyzed by the
calcium-dependent enzyme peptidyl-arginine-deiminase (PAD) which can
change a positively charged arginine to a polar but neutral citrulline as the
result of a post-translational modification. ACPAs serve as a useful diagnostic
reference for patients with undifferentiated arthritis and provide an indication
of disease progression (Bizarre N, et al.,2013).
The ACPA-positive subset of RA is more aggressive clinical phenotype
than ACPA-negative subset. It is proved that ACPA-negative RA has different
genetic patterns and differential responses of immune cells to citrullinated
antigens from those of ACPA-positive subset. less effective treatment response
of methotrexate (MTX) or rituximab was observed in ACPA-negative subset
(Malmström et al., 2016)

Triggering stage
ACPA appearance is now widely used to diagnose and predict RA due to its
high specificity (>97%) in clinical practice. ACPA occurs as a result of an
abnormal antibody response to citrullinated proteins, including fibrin, vimentin,
fibronectin, Epstein-Barr Nuclear Antigen 1 (EBNA-1), α-enolase, type II
collagen, and histones, all of them are distributed throughout the whole body.
ACPA production has been associated with genetic lifestyle, and environmental
factors.
Gene–environment interaction influences the reactivity of autoantibodies to
citrullinated antigens in RA patients (Abbasifard et al., 2020)
 Figure 1: Triggering stage of RA

RA can be triggered in the potential trigger sites through the interaction

between the genes and environmental factors resulting in the production of
autoantibodies against citrullinated peptides. Citrullination is catalyzed by the
calcium-dependent enzyme PAD resulting in changing a positively charged
arginine to a polar but neutral citrulline as the result of a post-translational
modification. In RA, PAD can be secreted by the granulocyte and macrophage.
ACPA occurs as a result of an abnormal antibody response to a range of
citrullinated proteins, including fibrin, vimentin, fibronectin, Epstein-Barr
Nuclear Antigen 1, α-enolase, type II collagen, and histones, all of them are
distributed in the whole body. Many citrullination neoantigens would activate
MHC class II-dependent T cells that in turn would help B cells produce more
ACPA (Guo et al., 2018)

Maturation stage
This stage is beginning at the site of secondary lymphoid tissues or bone
marrow. it refers to the development of immune responses to endogenous
epitopes resulting from the release of self-antigens. The immune response to
autoantigens may exist outside the joints and take many years before disease
onset. In this stage, epitope spreading and a gradually increased titer of ACPA
can last several years before appearance of disease symptoms (Alpizar-
Rodriguez et al., 2017).
ACCP has a great importance in predicting the interval time to disease
onset. The production of ACPA reflects break of immunological tolerance. As
a result, many citrullination neoantigens would activate MHC class II-
dependent T cells that in turn would help B cells produce more ACPA resulting
in pain, bone loss, and inflammation in RA (Krishnamurthy et al., 2019),
(Wigerblad et al., 2015).

Targeting stage
RA in joints usually has synovitis occurring in symmetrical small joints.
after immune activation, Joint swelling occurs as a reflection of synovial
membrane inflammation. The synovial compartment is filled with leukocytes
and pro-inflammatory mediators that interact to produce an inflammatory
cascade, which is characterized by the interactions of fibroblast-like
synoviocytes (FLSs) with the cells of the immune system, including
monocytes, macrophages and mast cells as well as cells of adaptive immune
system such as T lymphocytes (cell-mediated immunity) and B cells (humoral
immunity). The two immune systems and their interactions are involved in the
development of ACPA-positive RA, which results in inflammation (chronic
synovitis) (Cutolo et al., 2021)
ACPA can enhance NF-kB activity and TNF-α production via binding to
surface-expressed citrullinated Grp78 enhancing the production of pro-
inflammatory mediators. The imbalances between pro-inflammatory M1
macrophage and anti-inflammatory M2 macrophage can also cause
inflammatory RA (Bae et al., 2012)
 Figure 2: Targeting stage of RA

Many cells and their cytokines play critical roles in the development of RA.
The synovial compartment is infiltrated by leukocytes and pro-inflammatory
mediators that are produced to induce an inflammatory cascade, which is
characterized by interactions of fibroblast-like synoviocytes with the cells of
the innate immune system, including monocytes, macrophages, mast cells,
dendritic cells, as well as cells of adaptive immune system such as T cells and
B cells. Endothelial cells contribute to the extensive angiogenesis. The
fulminant stage contains hyperplastic synovium, cartilage damage, bone
erosion, and systemic consequence. The destruction of the subchondral bone
can finally result in the degeneration of the articular cartilage as the result of a
decrease in osteoblasts and an increase in osteoclasts (Guo et al., 2018)

Fulminant stage

Hyperplastic synovium
Synovium is characterized by a mixture of macrophages and specialized
FLSs. Synovial cells secrete hyaluronic acid and lubricin for joint lubrication
and function and processing waste products. In RA, the dysfunction of FLS
leads to hyperplastic synovium (Sergijenko et al., 2016).

Cartilage damage
 Cartilage is a key component of synovial joints. It consists of chondrocytes
and highly organized extracellular matrix (ECM) and contains type II collagen
and glycosaminoglycans (GAGs). The hyperplastic synovium can cause major
damage to the cartilage in RA patients. The inflammatory signals which
released from the ECM, can further stimulate FLS activity. FLS synthesize
MMPs which is considered the predominant proteinase that degrades the
collagenous cartilage matrix which results in cartilage degradation (Pap &
Korb-Pap, 2015).

Bone erosion
Bone loss is an important pathological feature of RA which appears as
localized, periarticular and systemic bone loss. Bone loss is due to the increase
of osteoclasts and the suppression of osteoblasts. The responsible mechanism is
unknown. It remains unknown whether inflammation or autoimmunity is the
cause of bone damage (Okamoto et al., 2017)
Evidence for the traditional inflammatory theory is through tumor necrosis
factor alpha (TNF-α), IL-6, IL-1β, IL-17, and other inflammatory cytokines
involved in RA which can exert pro-osteoclastogenic effects and suppress bone
formation. The second possible pathway for bone loss in RA involves two
mechanisms for autoimmunity that can be responsible for structural bone
damage. The first mechanism is the formation of immune complex and Fc-
receptor-mediated osteoclast differentiation. The second is the formation of
anti-citrullinated antibodies against the most citrullinated protein, making
osteoclasts the ideal antigenic targets for anti-citrullinated protein antibodies
(ACPA) (Harre et al., 2012)

Systemic consequences
RA patients have elevated risk of cardiovascular problems. the main
mechanism is that cytokines increase endothelial activation and make
atheromatous plaques unstable. RA patients have reduced total cholesterol,
low-density and high-density cholesterol.
RA can also affect the brain by causing fatigue and reduced cognitive
function; the lungs by causing inflammatory and fibrotic disease; the exocrine
glands by causing secondary Sjogren’s syndrome; the skeletal muscles by
causing sarcopenia; and the bones by causing osteoporosis. Finally, RA
patients are at high risk of cancer, especially hematologic and kidney cancers
(Wu et al., 2014)
signs and symptoms of RA
It often begins with fever, malaise, arthralgias, and weakness before
progressing to joint inflammation and swelling. when symptoms get worse, it's
known as flares, and times when symptoms get better it's known as remission
("Rheumatoid Arthritis (RA) | Arthritis | CDC", 2022).
Signs and symptoms of RA may include the following: ("Rheumatoid
Arthritis (RA): Practice Essentials, Background, Pathophysiology", 2022)
Persistent symmetric polyarthritis of hands and feet (the hallmark feature)
Progressive articular deterioration
Extra-articular involvement may be caused
Difficulty performing daily activities
Pain and stiffness in more than one joint
Tenderness and swelling in more than one joint
The same symptoms on both sides of the body (both hands or both knees)
Weight loss
Fever
Fatigue and Weakness

Figure 3: RA symptoms (Weinhouse & Weinhouse, 2022)

Diagnosis

Rheumatoid arthritis can be difficult to diagnose in its early stages because

the early signs and symptoms is similar to many other diseases. There is no
particular blood test or physical finding to confirm the diagnosis.

the diagnosis can be made by using a combination of clinical, laboratory,

and imaging features.
laboratory studies in suspected RA including:
Erythrocyte sedimentation rate
C-reactive protein level
Complete blood count
Rheumatoid factor assay
Antinuclear antibody assay
Anti−cyclic citrullinated peptide and anti−mutated citrullinated vimentin
assays
Potentially useful imaging modalities include the following:
the first choice is Radiography: Hands, wrists, knees, feet, elbows,
shoulders, hips, cervical spine, and other joints
Magnetic resonance imaging: cervical spine
Ultrasonography of joints: Joints in addition to tendon sheaths, changes and
degree of vascularization of the synovial membrane
Joint aspiration and analysis of synovial fluid can be useful including the
following: Gram stain, Cell count, Culture and Assessment of overall
appearance ("Rheumatoid Arthritis: How Does Your Doctor Diagnose It?",
2022).
The physical examination should address the following: ("Rheumatoid
Arthritis (RA): Practice Essentials, Background, Pathophysiology", 2022)
Upper extremities (metacarpophalangeal joints, wrists, elbows and
shoulders)
Lower extremities (ankles, feet, knees and hips)
Cervical spine
During the physical examination, it is necessary to assess the following:
Stiffness
Tenderness
Pain on motion
Swelling
Deformity
Limitation of motion
Extra-articular manifestations
 Rheumatoid nodules
Treatment
RA treatment depends on medication and life style modifications. Treatment
for RA can be done through the use of medications that slow disease and
prevent joint deformity, called disease-modifying ant rheumatic drugs
(DMARDs). The second-line treatment is biological response modifiers
(biologicals). In addition to medications, people can manage their RA with
self-management strategies proven to reduce pain
and disability ("Rheumatoid Arthritis (RA) | Arthritis | CDC", 2022)

Managing Rheumatoid Arthritis with Dietary interventions

weight loss
There are many studies showing that most patients with RA are above
normal weight. Most RA patients have an increased body fat and a decreased
muscle mass. the causes behind that is the inactivity imposed by a painful and
crippling joint disease. The inactivity reduces energy expenditure and can lead
to muscle atrophy. Another contributing factor is the use of medications such
as glucocorticoids which results in increased appetite and fat accumulation.
Their increased body weight has important implications for these patients. one
of them is the mechanical burden imposed on the joints, especially those of
the lower limbs, which are already weakened by chronic inflammation. They
will suffer structural damage more easily than normal people leading to
secondary osteoarthritis. It become very important to RA patients to follow a
healthy diet in order to be in their ideal weight (Zarpellon et al., 2014)
Figure 4:Dietary strategies to manage RA (Khanna et al., 2017)
vegan Diet
It is a diet including intake of only fruits and vegetables with eliminating
any animal product it is reported to be clinically beneficial for disease
remission in RA patients. Studies showed that this diet could improve the
disease activity by reducing the immune- reactivity to some food antigens that
were eliminated by changing the diet. The improvement was shown as decrease
in duration of morning stiffness, articular index, concentrations of acute-phase
reactants such as orosomucoid, C3 and haptoglobin. Moreover, the release of
lysozyme which are known to cause inflammation and destruction of joints was
decreased in RA patients following this diet.
Leukotriene B4 (LTB4) which is a pro-inflammatory mediator, involved in
activation of neutrophils, eosinophils, and monocytes, production of
proinflammatory cytokines, leading to tissue inflammation and neutrophil-
mediated tissue damage was also decreased by the end of the fasting week.
Furthermore, it has been reported that during starvation, ketone bodies,
including β-hydroxybutyrate (BHB), increase and serve as an alternate source
of ATP in these patients (Newman & Verdin, 2014). Other studies reported
inhibition of activation of NLRP3 inflammasomes by BHB in response to
various NLRP3 activators which reduced NLRP3-mediated release of IL-1β
and IL-18 from human monocytes which is playing an important anti-
inflammatory role (Youm et al., 2015).

Mediterranean Diet
Mediterranean diet is a diet that depends on high consumption of olive oil,
cereals, fruits, vegetables, fish, and legumes, less red meat and inclusion of
moderate amount of red wine in diet. studies showed that RA inflammation
was reduced, vitality and physical functions were improved in patients
following Mediterranean diet. MD depends mainly on olive oil which has
antioxidant properties and rich in oleic acid (18:1n-9) which is metabolized to
form eicosatrienoic acid (20:3n-9) and has strong anti-inflammatory effects.
olive oil also can suppress phosphorylation of STAT-3 and thus repressing IL-
17 production in order to decrease inflammation (Khanna et al., 2017). It can
also reduce translocation of p65 to nucleus thus reducing NF-κβ mediated
activation of various pro-inflammatory genes including TNF-α, IL-17, IL-6,
and IL-1β within arthritic joint which will influence osteoclast differentiation
thus promoting joint destruction. moreover, reduction in NF-κβ mediated
activation of pro-inflammatory cytokines will minimize joint destruction in RA
patients. A study proved that mice fed with olive oil had reduced cartilage
destruction and joint edema, thus, olive oil may be beneficial for RA patients
(Rosillo et al., 2015)
 (Chiara et al.,2020)

Elemental Diet
Elemental diet depends mainly on glucose, vitamins, trace elements, and
essential amino acids so it is hypoallergenic diet contains all nutrients for daily
requirements but it is less immunogenic (71). In a clinical trial, RA patients
were given an elemental diet (E028) providing 86 kcal and 2.5 g protein/100 ml
liquid elemental diet for 2 weeks. 72%of patients taking this elemental diet had
more than 20% improvement in early morning stiffness, and the Ritchie
articular index (RAI). The study concluded that this diet has the same effect as
15 mg/day of oral prednisolone (Khanna et al., 2017)
Elimination Diet
The aim of this diet is to eliminate the food related antigens that may
possibly aggravate the disease symptoms. Many studies concluded that food
allergens are potential triggers of
the immune system leading to inflammation by the activation of macrophage
and other inflammatory mediators. Treatment of RA includes inhibition of
TNF-α and IL-1, and these inflammatory mediators are observed to be
increased with the intake of allergenic food so excluding some of these food
from RA patient’s diet will help them to improve their disease condition and
reduce their requirement of medications such as: recombinant human IL-1
receptor antagonist and anti-TNF-α antibodies (Berin & Sampson, 2013)
Seven days fasting followed by vegan diet
some important studies showed that 7 to 10 days fasting cause a transient
immunosuppression, thereby suppressing RA through decreasing T cell
activation. these studies showed remarkable decrease in swollen and tender
joints, pain, erythrocyte sedimentation rate (ESR), and C-reactive
protein (CRP) (Tripathy et al., 2017)
Figure 5:Recommended Foods with Anti-Inflammatory Actions(Khanna et al.,
2017)
Essential Fatty Acids
Omega-3 or omega-6 fatty acids have a great role as immunosuppressants
and anti-inflammatory agents. Borage seed oil contains high amount of omega-
6 fatty acid or gamma-linolenic acid (GLA). A study showed that GLA had
significantly reduced tenderness and swallowing of joints in a group of RA
patients were taking it regularly (Tasset-Cuevas et al., 2013)
Fish oils contain high amount of omega-3 fatty acids which have a great
efficacy to treat RA. The group of RA patients which received fish oil had
reduced morning stiffness. Eicosapentaenoic and docosahexaenoic acids are
ethyl ester derivatives of omega-3 fatty acids, have the ability to reduce
severity of RA. When RA patients consumed these derivatives in an amount of
130 mg/kg body weight/day for 26–30 weeks, a significant decrease in pain,
morning stiffness and tenderness of joints was observed (Khanna et al., 2017)
Seven days fasting followed by vegan diet
some important studies showed that 7 to 10 days fasting cause a transient
immunosuppression, thereby suppressing RA through decreasing T cell
activation. these studies showed remarkable decrease in swollen and tender
joints, pain, erythrocyte sedimentation rate (ESR), and C-reactive
protein (CRP) (Tripathy et al., 2017)

Green tea
The main phytochemical in green tea is Epigallocatechin-3-gallate (EGCG).
EGCG has shown its ability to downregulate Mcl-1 in synovial fibroblasts and
increases the susceptibility toward apoptosis. Moreover, EGCG can suppress
the production of MMP-1, MMP-2, and MMP-3 in synovial fibroblasts and
prevents bone and cartilage destruction. It can also inhibit IL-1β induced IL-6
production by synovial fibroblast which in turn suppresses IL-6 trans signaling
resulting in reduction in inflammation caused by RA (Dragos et al., 2017)
Probiotics
probiotics have been shown to lower the proinflammatory cytokine IL-6 in
RA patients but the main mechanism remains unclear. The expected
mechanism is that Probiotics contain living healthy bacteria such as Bifid
bacteria, Bacteroides-Porphyromonas-Prevotella, Bacteroides fragilis and the
Eubacterium Rectal-Clostridium coccoides species which lead to a healthier
gut microbiota leading to less active immune system and inflammatory
reactions in the gut and finally leading to less inflammation systemically
(Catrina et al., 2014)

Spices
In a study, a mixture of blended ginger and turmeric were given to the
adjuvant-induced arthritic rats showed a great effect against extra-articular
complications of RA (Ramadan & El-Menshawy, 2013)
Curcumin is a potent anti-inflammatory spice through blocking the
expression of IL-1 and IL-6(Kloesch,et al.,2013)
Bark of Cinnamomum zeylanicum (Cinnamon bark) showed a great
inhibitory effects on secretion of cytokines IL-2, IL-4, and IFN-γ and reduction
in levels of TNF-α resulting in reducing the inflammation caused by RA (Rathi
et al., 2013)
Conclusion
RA is a very common disease which need great attention to discover new
treatment strategies. With the growing evidences supporting the positive impact
of diet strategies in decreasing disease activity in RA patients, with increasing
understanding of the beneficial effects of nutrients on inflammation and
immunity, our interest in dietary interventions is increasing.
Patients are always interested in alternative treatments to relieve their
condition so We should give great attention to diet therapy for RA patients. in
addition to the regular DMARDs and anti-TNFs that are provided for effective
cure of severe RA, patients should be encouraged to change their eating habits.
they should be aware with the benefits of eating more vegetarian/vegan diets,
eliminate potentially allergic food components, and take more poly unsaturated
fatty acid/oleic acid/symbiotic in their diet plans. these dietary interventions
can delay the early signs of RA which relieve RA patients. These foods are not
expensive but have a great impact on these patients so they can take it
regularly.
The ideal meal for RA patient should include raw or moderately cooked
vegetables (lots of greens, legumes, with addition of spices like turmeric and
ginger, seasonal fruits, probiotic yogurt; all of which will give them natural
antioxidants and have anti-inflammatory effects. The patient should avoid any
processed food, high salt, oils, butter, sugar, and animal products. Dietary
supplements like vitamin D, cod liver oil, and multivitamins can also help in
managing RA. This diet therapies may help patients to reduce their disease
activity, delay their disease progression, and reduce joint damage.
References:
1. Khanna, S., Jaiswal, K., & Gupta, B. (2017). Managing Rheumatoid
Arthritis with Dietary Interventions. Frontiers in Nutrition, 4.
https://doi.org/10.3389/fnut.2017.00052
2. Zarpellon, R., Dias, M., & Skare, T. (2022). Nutritional profile in
rheumatoid arthritis. Retrieved 16 January 2022, from.
http://dx.doi.org/10.1016/j.rbre.2014.02.011
3. Pereira IA , da Mota LMH, Cruz BA, Brenol CV, RezendeFronza LS,
Bertolo MB et al. 2012 Brazilian Society
of Rheumatology Consensus on the management of comorbidities in
patients with rheumatoid arthritis. Rev
Bras Reumatol 2012; 52: 474-95.
4. Rheumatoid Arthritis (RA) | Arthritis | CDC. Cdc.gov. (2022). Retrieved
16 January 2022, from https://www.cdc.gov/arthritis/basics/rheumatoid-
arthritis.html.
5. Bizarre N, et al. Anti-cyclic citrullinated peptide antibody titer predicts
time to rheumatoid arthritis onset in patients with undifferentiated
arthritis: results from a 2-year prospective study. Arthritis Res.
Ther. 2013;15: R16
6. Malmström, V., Catrina, A., & Klareskog, L. (2016). The
immunopathogenesis of seropositive rheumatoid arthritis: from
triggering to targeting. Nature Reviews Immunology, 17(1), 60-75.
https://doi.org/10.1038/nri.2016.124
7. Abbasifard, M., Imani, D., & Bagheri‐Hosseinabadi, Z. (2020). PTPN22
gene polymorphism and susceptibility to rheumatoid arthritis (RA):
Updated systematic review and meta‐analysis. The Journal Of Gene
Medicine, 22(9). https://doi.org/10.1002/jgm.3204
8. Guo, Q., Wang, Y., Xu, D., Nossent, J., Pavlos, N., & Xu, J. (2018).
Rheumatoid arthritis: pathological mechanisms and modern
pharmacologic therapies. Bone Research, 6(1).
https://doi.org/10.1038/s41413-018-0016-9
9. Alpizar-Rodriguez, D., Mueller, R., Moller, B., Dudler, J., Ciurea, A., &
Zufferey, P. et al. (2017). Female hormonal factors and the development
of anti-citrullinated protein antibodies in women at risk of rheumatoid
arthritis. Rheumatology, 56(9), 1579-1585.
https://doi.org/10.1093/rheumatology/kex239
10. Krishnamurthy, A., Joshua, V., Haj Hensvold, A., Jin, T., Sun, M., &
Vivar, N. et al. (2019). Identification of a novel chemokine-dependent
molecular mechanism underlying rheumatoid arthritis-associated
autoantibody-mediated bone loss. Annals of The Rheumatic
 Diseases, 75(4), 721-729. https://doi.org/10.1136/annrheumdis-2015-
208093
11. Wigerblad, G., Bas, D., Fernades-Cerqueira, C., Krishnamurthy, A.,
Nandakumar, K., & Rogoz, K. et al. (2015). Autoantibodies to
citrullinated proteins may induce joint pain independent of
inflammation. Annals of The Rheumatic Diseases, 75(4), 730-738.
https://doi.org/10.1136/annrheumdis-2015-208094
12. Cutolo, M., Sodano, S., Gotelli, E., Montagne, P., Campitiello, R., &
Palomino, S. et al. (2021). CTLA4-Ig treatment induces M1–M2 shift in
cultured monocyte-derived macrophages from healthy subjects and
rheumatoid arthritis patients. Arthritis Research & Therapy, 23(1).
https://doi.org/10.1186/s13075-021-02691-9
13. Bae, S., Kim, H., Lee, N., Won, C., Kim, H., & Hwang, Y. et al. (2012).
α-Enolase Expressed on the Surfaces of Monocytes and Macrophages
Induces Robust Synovial Inflammation in Rheumatoid Arthritis. The
Journal of Immunology, 189(1), 365-372.
https://doi.org/10.4049/jimmunol.1102073
14. Sergijenko, A., Roelofs, A., Riemann, A., & De Bari, C. (2016). Bone
marrow contribution to synovial hyperplasia following joint surface
injury. Arthritis Research & Therapy, 18(1).
https://doi.org/10.1186/s13075-016-1060-8
15. Pap, T., & Korb-Pap, A. (2015). Cartilage damage in osteoarthritis and
rheumatoid arthritis—two unequal siblings. Nature Reviews
Rheumatology, 11(10), 606-615.
https://doi.org/10.1038/nrrheum.2015.95
16. Okamoto, K., Nakashima, T., Shinohara, M., Neighs-Koga, T.,
Komatsu, N., & Terashima, A. et al. (2017). Osteoimmunology: The
Conceptual Framework Unifying the Immune and Skeletal
Systems. Physiological Reviews, 97(4), 1295-1349.
https://doi.org/10.1152/physrev.00036.2016
17. Harre, U., Georges, D., Bang, H., Bozec, A., Axmann, R., & Ossipova,
E. et al. (2012). Induction of osteoclast genesis and bone loss by human
autoantibodies against citrullinated vimentin. Journal of Clinical
Investigation, 122(5), 1791-1802. https://doi.org/10.1172/jci60975
18. Wu, C., Chen, D., Shen, J., Ho, H., Chen, C., & Kuo, K. et al. (2014).
The risk of cancer in patients with rheumatoid arthritis taking tumor
necrosis factor antagonists: a nationwide cohort study. Arthritis
Research & Therapy, 16(5). https://doi.org/10.1186/s13075-014-0449-5
19. Rheumatoid Arthritis (RA): Practice Essentials, Background,
Pathophysiology. Emedicine.medscape.com. (2022). Retrieved 16
 January 2022, from https://emedicine.medscape.com/article/331715-
overview.
20. Winehouse, B., & Winehouse, B. (2022). Rheumatoid Arthritis
Symptoms: 15 Clues You Might Be Ignoring. Creaky Joints. Retrieved
17 January 2022, from https://creakyjoints.org/about-
arthritis/rheumatoid-arthritis/ra-symptoms/rheumatoid-arthritis-signs-
and-symptoms/.
21. Rheumatoid Arthritis: How Does Your Doctor Diagnose It? WebMD.
(2022). Retrieved 16 January 2022, from
https://www.webmd.com/rheumatoid-arthritis/diagnosing-ra.
22. Rheumatoid Arthritis (RA) | Arthritis | CDC. Cdc.gov. (2022). Retrieved
17 January 2022, from https://www.cdc.gov/arthritis/basics/rheumatoid-
arthritis.html.
23. Zarpellon, R., Dias, M., & Skare, T. (2014). Nutritional profile in
rheumatoid arthritis. Revisit Brasilia De Rheumatologic (English
Edition), 54(1), 68-72. https://doi.org/10.1016/j.rbre.2014.02.011
24. Tasset-Cuevas, I., Fernández-Bedmar, Z., Lozano-Baena, M., Campos-
Sánchez, J., de Haro-Bailón, A., Muñoz-Serrano, A., & Alonso-Moraga,
Á. (2013). Protective Effect of Borage Seed Oil and Gamma Linolenic
Acid on DNA: In Vivo and In Vitro Studies. Plos ONE, 8(2), e56986.
https://doi.org/10.1371/journal.pone.0056986
25. Khanna, S., Jaiswal, K., & Gupta, B. (2017). Managing Rheumatoid
Arthritis with Dietary Interventions. Frontiers In Nutrition, 4.
https://doi.org/10.3389/fnut.2017.00052
26. Tripathy, A., Khanna, S., Padhan, P., Smita, S., Raghav, S., & Gupta, B.
(2017). Direct recognition of LPS drive TLR4 expressing CD8+ T cell
activation in patients with rheumatoid arthritis. Scientific Reports, 7(1).
https://doi.org/10.1038/s41598-017-01033-7
27. Catrina AI, Deane KD, SC her JU. Gene, environment, microbiome
and mucosal immune tolerance in rheumatoid arthritis.
Rheumatology 2016;55:391–402
28. Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends
Endocrinal Me tab (2014) 25(1):42–52. doi:10.1016/j.tem.2013.09.002

29. Youm Y-H, Nguyen KY, Grant RW, Goldberg EL, Bodega M, Kim D,
et al.
The ketone metabolite [beta]-hydroxybutyrate blocks NLRP3
inflammasome-mediated inflammatory disease. Nat Med (2015)
21(3):263–9.
doi:10.1038/nm.3804
30. Rosillo, M., Sánchez-Hidalgo, M., Sánchez-Fidalgo, S., Aparicio-Soto,
M., Villegas, I., & Alarcon-de-la-Lustra, C. (2015). Dietary extra-virgin
olive oil prevents inflammatory response and cartilage matrix
degradation in murine collagen-induced arthritis. European Journal Of
Nutrition, 55(1), 315-325. https://doi.org/10.1007/s00394-015-0850-0
31. Berin MC, Sampson HA. Mucosal immunology of food allergy. Cur
Biol (2013) 23(9): R389–400. doi: 10.1016/j.cub.2013.02.043
32. Drago’s D, Gilca M, Gaman L, Vlad A, Iosif L, Stoian I, et al.
Phytomedicine in joint disorders. Nutrients (2017) 9(1):70.
doi:10.3390/nu9010070
33. Kloesch,et, et, et, et, et B, Becker T, Dietersdorfer E, Kiener H, Steiner
G. Anti-inflammatory and apoptotic effects of the polyphenol curcumin
on human fibroblast-like synoviocytes. Int Immunopharmacol (2013)
15(2):400–5. doi:10.1016/j. intimp.2013.01.003
34. Ramadan G, El-Menshawy O. Protective effects of ginger-turmeric
rhizomes mixture on joint inflammation, atherogenesis, kidney
dysfunction and other complications in a rat model of human
rheumatoid arthritis. Int J Rheum Dis (2013) 16(2):219–29.
doi:10.1111/1756-185X.12054
35. Rathi B, Bodhankar S, Mohan V, Thakurdesai P. Ameliorative effects of
a polyphenolic fraction of Cinnamomum zeylanicum L. bark in animal
models of inflammation and arthritis. Sci Pharm (2013) 81(2):567–90.
doi:10.3797/scipharm.1301-16
36. Oia, Chiara, Bruno Luciano, Maria G. Tarsitano, Cristina Iannuccelli,
and Manuela Di Franco. 2020. "Dietary Habits and Nutrition in
Rheumatoid Arthritis: Can Diet Influence Disease Development and
Clinical Manifestations?" Nutrients 12, no. 5: 1456.
https://doi.org/10.3390/nu12051456