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Nagaraju et al. World Journal of Pharmaceutical

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REVIEW ON RHEUMATOID ARTHRITIS AND AWARENESS ON MULTIPLE

CATEGORIES

G. Sirisha1, Dr. G. Nagaraju1*, J. Keerthi2, M. Suhasya3, S. Laxmi Prasanna4 and T. Satish Kumar5
1
Assoc. Professor Dhanvanthari Institute of Pharmaceutical Sciences, Sujatha Nagar, Kothagudem.
1
Principal of DhanvanthariInstitute of Pharmaceutical Sciences, Sujatha Nagar, Kothagudem.
2,3,4,5
B. Pharmacy IV year students of Dhanvanthari Institute of Pharmaceutical Sciences, Sujatha Nagar, Kothagudem.

*Corresponding Author: Dr. G. Nagaraju

Principal of Dhanvanthari Institute of Pharmaceutical Sciences, Sujathanagar, Kothagudem.

Article Received on 05/02/2025 Article Revised on 25/02/2025 Article Accepted on 17/03/2025

ABSTRACT
Rheumatoid arthritis (RA), a chronic inflammatory autoimmune disorder, is characterised by persistent synovial
inflammation, erosion of bones and cartilage, leading to joint destruction. Clinical manifestations are morning
stiffness, pain in shoulder, neck and pelvic girdle, loss of mobility with fever, fatigue, malaise, loss of body weight,
and development of rheumatoid nodules. Environmental and genetic factors are important contributors in its
susceptibility. Association between RA and diet, cigarette smoking, hormones, alcohol, microbiota, infection, and
coffee have also been reported. To diagnose patients with RA, American college of rheumatology (ACR, 2010)
criteria, developed by European league against rheumatism (EULAR). Inflammation produced in RA patients is
due to cell-mediated immune response. The rheumatoid synovium consists of a large number of CD 4+ T cells
suggesting pathogenic nature of T cells in this disorder. B-cells may also participate in the pathogenesis by several
means such as autoantibodies, by instigation of T-cells through expression of co-stimulatory molecules, by
generating pro-inflammatory and anti-inflammatory cytokines and by organisation of other inflammatory cells. The
conventional management of RA usually focuses over reducing pain and limiting the disability by medical
therapies which include a number of classes of agents such as non-steroidal anti-inflammatory drugs (NSAIDs),
non-biological and biological agents, disease-modifying anti rheumaticdrugs (DMARDs), immunosuppressants,
and corticosteroids. However, only proper rehabilitation can promote the objective to achieve the joint functionality
and ease of motion which improves independence as well as quality of life in patient suffering from Rheumatoid
Arthritis.

KEYWORDS: rheumatoid arthritis, joints deformity, autoimmune disorder, NSAIDs and DMARDs.

Significance of the Study patient. Common symptoms of RA include morning

Rheumatoid arthritis not only affects the joints but can stiffness of the affected joints for > 30 min, fatigue,
also affect internal organs, thus causing permanent fever, weight loss, joints that are tender, swollen and
disability in many instances. Currently, there is no cure warm, and rheumatoid nodules under the skin. The onset
for this autoimmune disease, rather, symptoms are of this disease is usually from the age of 35 to 60 years,
addressed on an individual basis. Here, we succinctly with remission and exacerbation. It can also afflict young
summarize the classic and current treatment options children even before the age of 16 years, referred to as
available for the management of patients suffering from juvenile RA (JRA), which is similar to RA except that
this complex disease. rheumatoid factor is not found.[2, 3, 4, 5] In the West, the
prevalence of RA is believed to be 1–2%[5, 6], and 1%
INTRODUCTION worldwide.[7]
Rheumatoid arthritis (RA) is a chronic, symmetrical,
inflammatory autoimmune disease that initially affects Clinically, the diagnosis of RA can be differentiated from
small joints, progressing to larger joints, and eventually osteoarthritis (OA) as the affected areas in RA are the
the skin, eyes, heart, kidneys, and lungs. Often, the bone proximal interphalangeal (PIP) and metacarpophalangeal
and cartilage of joints are destroyed, and tendons and (MP) joints; OA typically affects the distal
ligaments weaken.[1] All this damage to the joints causes interphalangeal (DIP) joint. OA is the most common type
deformities and bone erosion, usually very painful for a of arthritis and is caused by wear and tear rather than an

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Nagaraju et al. World Journal of Pharmaceutical and Life Science

autoimmune condition. It has no effects on the lungs, Etiology: The etiology of RA has a significant basis in
heart, or immune system. In addition, OA typically genetics. It is thought to result from the interaction
affects only one side of the body, as opposed to the between patients' genotypes and environmental factors.
symmetrical nature of RA. Another differentiating factor In a nationwide study of 91 monozygotic (MZ) and 112
is that RA patients suffer from persistent morning dizygotic (DZ) twin pairs in the United Kingdom, the
stiffness for at least ≥1 h. Patients with OA may have overall MZ concordance rate was 15%, and in dizygotic
morning stiffness, but this typically resolves or decreases twins, 5%.[19] The heritability of rheumatoid arthritis is
within 20–30 min.[8, 9] The goals of treatment for RA are approximately 40% to 65% for seropositive rheumatoid
to reduce joint inflammation and pain, maximize joint arthritis and 20% for seronegative rheumatoid
function, and prevent joint destruction and deformity. arthritis.[19] The risk of developing rheumatoid arthritis
Treatment regimens consist of combinations of has been associated with HLA-DRB1 alleles: HLA-
pharmaceuticals, weight-bearing exercise, educating DRB1*04, HLA-DRB1*01, and HLA-DRB1*10. These
patients about the disease, and rest. Treatments are HLA-DRB1 alleles contain a stretch of a conserved
generally customized to a patient's needs and depend on sequence of 5 amino acids referred to as the "shared
their overall health. This includes factors such as disease epitope" (SE) in the third hypervariable region of their
progression, the joints involved, age, overall health, DRB1 chain, which has been associated with the risk of
occupation, compliance, and education about the developing RA.[20][21][22][23]
disease.[10] This review briefly highlights the classic and
current treatment options available to address the Polymorphisms in other genes are associated with RA,
discomfort/complications of RA. An exhaustive review including PAD14, PTPN22, CTLA4, IL-2RA, STAT4,
was recently published by Smolen et al.[11] TRAF1, CCR6, and IRF5.[24][25][26] Single nucleotide
polymorphism (SNP) in PSORS1C1, PTPN22,
PATHOPHYSIOLOGY OF RHEUMATOID and MIR146A genes are associated with severe
ARTHRITIS disease.[27] Some genetic polymorphisms are associated
RA, in some patients, is triggered by some sort of with RA in different ethnic groups.[25][27]
environmental factor in a genetically predisposed host.
The best example is tobacco use in a patient with the The term epigenetics refers to heritable changes without
HLA-DRB1 "shared epitope" gene and the development altering the DNA sequence. These changes may be
of ACPA-positive RA.[12] RF and ACPA antibodies are present in chromatin or the DNA. These include DNA
the best-known autoantibodies in RA, but several other methylation, histone modification, and non-coding RNA-
autoantibodies are relatively specific for RA. The mediated regulation. RA-FLS (fibroblast-like
presence of antibodies in rheumatoid arthritis is referred synoviocytes) overexpress tyrosine phosphatase SHP-2,
to as seropositive RA. RF is an antibody of any isotype coded by gene PTPN11, compared to synoviocytes from
that binds to the Fc portion of IgG RA patients often osteoarthritis (OA) patients, promoting the invasive
have antibodies to citrullinated proteins. These nature of RA-FLS. The enhancer region of the PTPN11
antibodies have been identified in patients with RA since intron contained two hypermethylated sites, resulting in
1964 (antiperinuclear factor)[13] and were also described abnormal epigenetic regulation of the gene and alteration
in 1979 (anti-keratin antibodies)[14] by different assays. of the function of RA-FLS.[28]
In the 1990s, these antibodies were determined to be the
same antibodies with high specificity for RA. Cigarette smoking is the strongest environmental risk
factor associated with rheumatoid arthritis. Studies have
[15]
The antibodies were found to have specificity for shown in anti-citrullinated protein antibody (anti-CCP)
filaggrin, a citrullinated peptide.[16][15] The epitope for positive individuals, there is an interaction between the
these antibodies is citrullinated peptides. A cyclic shared epitope (SE) and smoking that increases the risk
citrullinated peptide (CCP) was synthesized, which could of RA.[29][30][31][32][33][34][35]
be used in an ELISA to test for these antibodies in
patients in a clinical situation.[17] These antibodies are Other environmental triggers may play a role as a trigger
called anti-cyclic citrullinated peptide antibodies for RA, which is more closely associated with
(ACPA). Citrulline is derived from the post- seropositive RA. These include silica, asbestos, textile
transcriptional modification of arginine by peptidyl dust, and P gingivalis.[36] This suggests that external
arginine deiminase (PAD).[18] exposure to various antigens in parts of the host distant
from the joints then triggers an autoimmune
The immune response in RA starts at sites distant from inflammatory response in the joints. These distant
the synovial joints, such as the lung, gums, and GI locations include the lungs, oropharynx, and GI tract. [36]
tract.[12] In these tissues, modified proteins are produced Changes in the composition and function of the intestinal
by biochemical reactions such as citrullination. The microbiome have been related to rheumatoid arthritis as
mechanism behind environment-triggered RA is thought well. The composition of the gut microbiome becomes
to be due to the repeated activation of innate immunity. altered in patients with rheumatoid arthritis (dysbiosis),
where rheumatoid arthritis patients have decreased gut
microbiome diversity compared with healthy individuals.

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Nagaraju et al. World Journal of Pharmaceutical and Life Science

There is an increase in these genera: Actinobacteria, tissues to harmful stimuli, such as pathogens, damaged
Collinsella, Eggerthalla, and cells, or irritants (Fig.8). Inflammation is a protective
Faecalibacterium. Collinsella alters gut mucosal attempt by the organism to remove the injurious stimuli
permeability and has been related to increased and to initiate the healing process. Inflammation is not a
rheumatoid arthritis disease severity.[35] synonym for infection, even in cases where inflammation
is caused by infection. Although infection is caused by a
Mechanism of Action microorganism, inflammation is one of the responses of
By inhibiting fatty acid COX enzyme, trolamine the organism to the pathogen. However, inflammation is
salicylate inhibits the production of prostaglandins and a stereotyped response, and therefore it is considered as a
thromboxanes in inflammatory cells involved in mechanism of innate immunity, as compared to adaptive
generating pain and inflammation.[17] immunity, which is specific for each pathogen.

Inflammation
Inflammation (Latin, inflammo, "I ignite, set alight") is
part of the complex biological response of vascular

Fig. 8: Inflammation

Classification of Inflammation The cause of RA is unknown, but certain risk factors are
Inflammation can be classified as either acute or chronic. associated with an increased likelihood of developing
Acute inflammation is the initial response of the body to RA, including a family history of RA or other
harmful stimuli and is achieved by the increased autoimmune diseases, smoking, poor dental health, and
movement of plasma and leukocytes (especially viral infections.
granulocytes) from the blood into the injured tissues. A
cascade of biochemical events propagates and matures Diagnosis of RA
the inflammatory response, involving the local vascular  Medical history: The doctor will ask about joint
system, the immune system, and various cells within the symptoms (pain, tenderness, stiffness, difficulty
injured tissue. Prolonged inflammation, known as moving), when they started, if they come and go,
chronic inflammation, leads to a progressive shift in the how severe they are, what actions make them better
type of cells present at the site of inflammation and is or worse and whether family members have RA or
characterized by simultaneous destruction and healing of another autoimmune disease.
the tissue from the inflammatory process.[45]  Physical examination: The doctor will look for
joint tenderness, swelling, warmth and painful or
Signs and symptoms limited movement, bumps under the skin or a low-
Signs and symptoms of RA usually occur in the wrists, grade fever.
hands, or feet and include:  Rheumatologists use physical examination, blood
 pain, swelling, and stiffness in more than one joint tests, and x-ray scans to diagnose RA. Most patients
 a low-grade fever with RA have blood test results that are positive for
 appetite loss antibodies called rheumatoid factor (RF), anticyclic
 weight loss citrullinated protein (CCP) antibodies, or both.
 tiredness Rheumatologists can help differentiate RA from
 dry eyes other diseases that may cause similar symptoms but
 chest pain. require different treatment.

Risk Factors for RA Treatment and Prognosis of RA

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

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Nagaraju et al. World Journal of Pharmaceutical and Life Science

NSAIDs do not have any disease-modifying effects but 3. Which type of diet you're taking after suffering?
are commonly used to relieve symptoms related to joint 4. If you have any other disease along with rheumatoid
inflammation and pain. There are about 20 such drugs arthritis?
(depending on what country you are in) that are all 5. When was this condition first diagnosed?
effective at full doses. There is some variation in side 6. Which type of drugs your using?
effects and toxicities. There is a class Black Box warning 7. From how many years you're suffering from
for cardiovascular disease, although there is variation in rheumatoid arthritis?
the cardiovascular effects among NSAIDs.[37][38] 8. Are you suffering difficulty while holding objectives?
9. What did you think the cause of rheumatoid arthritis
 Corticosteroids
Corticosteroids are commonly used in patients with RA. 10. You taking prescribed medicines or medications?
There are several situations in which corticosteroids A) Yes
should be considered. In a new patient with very active B) No
RA, corticosteroids can be used as bridge therapy while [Link] you skip any medications in last few days during
DMARD therapy is instituted. Some studies show that disease period?
using corticosteroids early in RA patients improves A) Yes
outcomes and has disease-modifying effects, including B) No
radiographic progression.[39][40] 12. Did you stop taking your medications or medicines
when you drink alcoholic beverages?
TNF inhibitors A) Yes
The TNF inhibitors include etanercept, infliximab, B) No
adalimumab, certolizumab, and golimumab. The ACR
does not recommend using TNF inhibitors until a RESULT
nonbiologic DMARD has been tried.[41] We limited analysis to individuals 20 years and older and
excluded those who did not have a medical exam
Rituximab because this provided BMI data. Respondents were
Rituximab is a biologic DMARD that can be added for asked if they had arthritis, and if so, was it OA, RA,
treating RA if patients have uncontrolled RA and who psoriatic arthritis (PA), other arthritis, and whether they
did not respond to TNF inhibitors.[42] Rituximab is given did not know what kind. While it is likely that most who
as an intravenous infusion; it depletes CD20+ B-cells reported that they did not know what kind had OA, we
and decreases the immune response to vaccines in excluded these from further consideration because our
patients receiving rituximab. goal was a comparison of risks for confirmed OA and
RA. We also lumped those with PA in with “other”
Janus kinase (JAK) Inhibitors because those numbers were small. Over the full period
JAK is a group of tyrosine kinases that participate in there were 47,031 persons who had the medical exam
intracellular signal transduction for haematopoiesis and and were included in our study. Of these there were
immune cell function. JAK inhibitors (such as 4,298 reported cases of OA, 2,482 reported case of RA,
tofacitinib) are oral agents that reduce the production of 1,337 individuals with other types of arthritis, and 4,218
cytokines and are approved as second-line agents for the individuals who did not know what type of arthritis they
treatment of RA.[43] had. A total of 34,696 persons reported that they did not
suffer from arthritis.
PREVANTION
Several key prevention strategies have been proposed to DISCUSSION
prevent rheumatoid arthritis and control the disease Prevalence of both increases with age, although it rises
progression. In particular, reducing exposure to inhaled more steeply at older age for OA as would be expected
silica, dusts and occupational risks, and lifestyle related due to wear and tear. Both occur more frequently in
behaviours (e.g., prevention of/stop smoking, healthy women than men. However, the sex difference we find
nutrition, physical activity, maintaining a normal body using NHANES data is not nearly as large as literature
weight, maintaining good dental hygiene) play an reports of a three-fold difference (Wolfe et al., 1968).
important role. Some evidence also suggests The reasons for this are unclear. One possibility is that
breastfeeding may be protective to the mother the random survey used by NHANES provides a more
accurate distribution than seen in a hospital or
ANNEXURE clinicbased study, which often reflects greater use of
SURVEY QUESTIONNAIRE medical care by women than by men. Nevertheless, we
[Link]: do find rates in women to be higher than men.
Age:
Gender: CONCLUSION
Working: RA is a debilitating, chronic, inflammatory disease,
2. What is the past history of the rheumatoid arthritis in capable of causing joint damage as well as long-term
your family? disability. Early diagnosis and intervention are essential

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Nagaraju et al. World Journal of Pharmaceutical and Life Science

for the prevention of serious damage and loss of essential arthritis: implications for pathogenesis and treatment
bodily functions. The treating physician should consider in the biologic therapy era. Rheumatology (Oxford),
adhering to treat-to-target (T2T) recommendations [44], 2015 Jan; 54(1): 29–38. doi:
by first outlining the aims and then implementing the 10.1093/rheumatology/keu328. [DOI] [PMC free
protocols to achieve and assess them. Furthermore, early article] [PubMed] [Google Scholar]
referral to a specialist can help to ensure better treatment 9. Piyarulli D, Koolaee RM. A 22-Year-Old Female
outcomes. With advances in the field of molecular with Joint Pain. In: Piyarulli D, Koolaee RM,
medicine, we have a better understanding of disease editors. Medicine Morning Report: Beyond the
mechanisms which can aid in the designing of more Pearls. Cambridge: Elsevier, 2016; 65–77. [Google
effective treatments. Old treatment modalities have been Scholar]
optimized and new ones have been produced. Gene array 10. Staheli LT. Lower extremity management. In:
analysis is proving beneficial in finding out which Staheli LT, Hall JG, Jaffe KM, Paholke DO, editors.
patients will be more responsive to specific medications. Arthrogryposis: A Text Atlas. Cambridge:
This customization will allow for more rapid treatment Cambridge University Press, 1998; 55–73. [Google
as well as decrease the likelihood of disease progression Scholar]
during the experimental phase to seek an appropriate 11. Smolen JS, Aletaha D, Barton A, Burmester GR,
treatment for a particular patient. Gene array analysis is Emery P, Firestein GS, et al. Rheumatoid arthritis.
also being used to determine which patients are at greater Nat Rev Dis Primers, 2018 Feb; 4: 18001. doi:
risk for more aggressive forms of RA. It is foreseen that 10.1038/nrdp.2018.1. [DOI] [PubMed] [Google
treatment methods will face tremendous improvements Scholar]
in the management of RA. 12. Klareskog L, Rönnelid J, Saevarsdottir S, Padyukov
L, Alfredsson L. The importance of differences; On
REFERENCES environment and its interactions with genes and
1. Lee JE, Kim IJ, Cho MS, Lee J. A Case of immunity in the causation of rheumatoid arthritis. J
Rheumatoid Vasculitis Involving Hepatic Artery in Intern Med., 2020 May; 287(5): 514-533. [PubMed]
Early Rheumatoid Arthritis. J Korean Med Sci., 13. NIENHUIS RL, MANDEMA E. A NEW SERUM
2017 Jul; 32((7): 1207–10. doi: FACTOR IN PATIENTS WITH RHEUMATOID
10.3346/jkms.2017.32.7.1207. [DOI] [PMC free ARTHRITIS; THE ANTIPERINUCLEAR
article] [PubMed] [Google Scholar] FACTOR. Ann Rheum Dis., 1964 Jul; 23(4): 302-5.
2. Fox CQ, Ahmed SS. Physician Assistant's Clinical [PMC free article] [PubMed]
Review Cards. Philadelphia: F. A. Davis Company, 14. Young BJ, Mallya RK, Leslie RD, Clark CJ,
2002; 138–139. [Google Scholar] Hamblin TJ. Anti-keratin antibodies in rheumatoid
3. McInnes IB, Schett G. The pathogenesis of arthritis. Br Med J., 1979 Jul 14; 2(6182): 97-9.
rheumatoid arthritis. N Engl J Med., 2011 Dec; [PMC free article] [PubMed]
365(23): 2205–19. doi: 10.1056/NEJMra1004965. 15. Sebbag M, Simon M, Vincent C, Masson-Bessière
[DOI] [PubMed] [Google Scholar] C, Girbal E, Durieux JJ, Serre G. The antiperinuclear
4. Chaudhari K, Rizvi S, Syed BA. Rheumatoid factor and the so-called antikeratin antibodies are the
arthritis: current and future trends. Nat Rev Drug same rheumatoid arthritis-specific autoantibodies. J
Discov. 2016 May; 15(5): 305–6. doi: Clin Invest., 1995 Jun; 95(6): 2672-9. [PMC free
10.1038/nrd.2016.21. [DOI] [PubMed] [Google article] [PubMed]
Scholar] 16. Hoet RM, Boerbooms AM, Arends M, Ruiter DJ,
5. Picerno V, Ferro F, Adinolfi A, Valentini E, Tani C, van Venrooij WJ. Antiperinuclear factor, a marker
Alunno A. One year in review: the pathogenesis of autoantibody for rheumatoid arthritis: colocalisation
rheumatoid arthritis. Clin Exp Rheumatol., 2015 Jul- of the perinuclear factor and profilaggrin. Ann
Aug; 33(4): 551–8. [PubMed] [Google Scholar] Rheum Dis., 1991 Sep; 50(9): 611-8. [PMC free
6. Alamanos Y, Voulgari PV, Drosos AA. Incidence and article] [PubMed]
prevalence of rheumatoid arthritis, based on the 17. 1991 Sep; 50(9): 611-8. [PMC free article]
1987 American College of Rheumatology criteria: a [PubMed]
systematic review. Semin Arthritis Rheum., 2006 18. Schellekens GA, Visser H, de Jong BA, van den
Dec; 36(3): 182–8. doi: Hoogen FH, Hazes JM, Breedveld FC, van Venrooij
10.1016/[Link].2006.08.006. [DOI] [PubMed] WJ. The diagnostic properties of rheumatoid arthritis
[Google Scholar] antibodies recognizing a cyclic citrullinated peptide.
7. Chopra A, Abdel-Nasser A. Epidemiology of Arthritis Rheum., 2000 Jan; 43(1): 155-63.
rheumatic musculoskeletal disorders in the [PubMed]
developing world. Best Pract Res Clin Rheumatol., 19. Van Delft MAM, Huizinga TWJ. An overview of
2008 Aug; 22(4): 583–604. doi: autoantibodies in rheumatoid arthritis. J
10.1016/[Link].2008.07.001. [DOI] [PubMed] Autoimmun., 2020 Jun; 110: 102392. [PubMed]
[Google Scholar] 20. Silman AJ, MacGregor AJ, Thomson W, Holligan S,
8. McGonagle D, Hermann KG, Tan AL. Carthy D, Farhan A, Ollier WE. Twin concordance
Differentiation between osteoarthritis and psoriatic rates for rheumatoid arthritis: results from a

[Link] │ Vol 11, Issue 4, 2025. │ ISO 9001:2015 Certified Journal │ 99

Nagaraju et al. World Journal of Pharmaceutical and Life Science

nationwide study. Br J Rheumatol., 1993 Oct; S, Breedveld FC, Toes RE, Huizinga TW. Smoking
32(10): 903-7. [PubMed] is a risk factor for anti-CCP antibodies only in
21. Wu H, Liao W, Li Q, Long H, Yin H, Zhao M, Chan rheumatoid arthritis patients who carry HLA-DRB1
V, Lau CS, Lu Q. Pathogenic role of tissue-resident shared epitope alleles. Ann Rheum Dis., 2006 Mar;
memory T cells in autoimmune 65(3): 366-71. [PMC free article]
diseases. Autoimmun Rev., 2018 Sep; 17(9): 33. Klareskog L, Stolt P, Lundberg K, Källberg H,
906-911. [PubMed] Bengtsson C, Grunewald J, Rönnelid J, Harris HE,
22. Weyand CM, Hicok KC, Conn DL, Goronzy JJ. The Ulfgren AK, Rantapää-Dahlqvist S, Eklund A,
influence of HLA-DRB1 genes on disease severity Padyukov L, Alfredsson L. A new model for an
in rheumatoid arthritis. Ann Intern Med., 1992 Nov etiology of rheumatoid arthritis: smoking may
15; 117(10): 801-6. [PubMed] trigger HLA-DR (shared epitope)-restricted immune
23. du Teil Espina M, Gabarrini G, Harmsen HJM, reactions to autoantigens modified by
Westra J, van Winkelhoff AJ, van Dijl JM. Talk to citrullination. Arthritis Rheum., 2006 Jan; 54(1):
your gut: the oral-gut microbiome axis and its 38-46. [PubMed]
immunomodulatory role in the etiology of 34. Lundström E, Källberg H, Alfredsson L, Klareskog
rheumatoid arthritis. FEMS Microbiol Rev., 2019 L, Padyukov L. Gene-environment interaction
Jan 01; 43(1): 1-18. between the DRB1 shared epitope and smoking in
24. Wu H, Liao W, Li Q, Long H, Yin H, Zhao M, Chan the risk of anti-citrullinated protein antibody-
V, Lau CS, Lu Q. Pathogenic role of tissue-resident positive rheumatoid arthritis: all alleles are
memory T cells in autoimmune important. Arthritis Rheum. 2009 Jun; 60(6):
diseases. Autoimmun Rev., 2018 Sep; 17(9): 1597-603. [PMC free article] [PubMed] [Reference
906-911. list]
25. Okada Y, Eyre S, Suzuki A, Kochi Y, Yamamoto K. 35. Sugiyama D, Nishimura K, Tamaki K, Tsuji G,
Genetics of rheumatoid arthritis: 2018 status. Ann Nakazawa T, Morinobu A, Kumagai S. Impact of
Rheum Dis., 2019 Apr; 78(4): 446-453. smoking as a risk factor for developing rheumatoid
26. Dedmon LE. The genetics of rheumatoid arthritis: a meta-analysis of observational
arthritis. Rheumatology (Oxford). 2020 Oct 01; studies. Ann Rheum Dis., 2010 Jan; 69(1):
59(10): 2661-2670. 70-81. [PubMed] [Reference list]
27. Padyukov L. Genetics of rheumatoid arthritis. Semin 36. Derksen VFAM, Huizinga TWJ, van der Woude D.
Immunopathol., 2022 Jan; 44(1): 47-62. [PMC free The role of autoantibodies in the pathophysiology of
article] rheumatoid arthritis. Semin Immunopathol., 2017
28. Ciccacci C, Conigliaro P, Perricone C, Rufini S, Jun; 39(4): 437-446. [PMC free article] [PubMed]
Triggianese P, Politi C, Novelli G, Perricone R, 37. Klareskog L, Rönnelid J, Saevarsdottir S, Padyukov
Borgiani P. Polymorphisms in STAT-4, IL-10, L, Alfredsson L. The importance of differences; On
PSORS1C1, PTPN2 and MIR146A genes are environment and its interactions with genes and
associated differently with prognostic factors in immunity in the causation of rheumatoid arthritis. J
Italian patients affected by rheumatoid arthritis. Clin Intern Med., 2020 May; 287(5): 514-533. [PubMed]
Exp Immunol., 2016 Nov; 186(2): 157-163. 38. Solomon DH, Husni ME, Wolski KE, Wisniewski
29. Stanford SM, Maestre MF, Campbell AM, Bartok B, LM, Borer JS, Graham DY, Libby P, Lincoff AM,
Kiosses WB, Boyle DL, Arnett HA, Mustelin T, Lüscher TF, Menon V, Yeomans ND, Wang Q, Bao
Firestein GS, Bottini N. Protein tyrosine W, Berger MF, Nissen SE., PRECISION Trial
phosphatase expression profile of rheumatoid Investigators. Differences in Safety of Nonsteroidal
arthritis fibroblast-like synoviocytes: a novel role of Antiinflammatory Drugs in Patients with
SH2 domain-containing phosphatase 2 as a Osteoarthritis and Patients with Rheumatoid
modulator of invasion and survival. Arthritis Arthritis: A Randomized Clinical Trial. Arthritis
Rheum., 2013 May; 65(5): 1171-80. Rheumatol., 2018 Apr; 70(4): 537-546.
30. Stolt P, Bengtsson C, Nordmark B, Lindblad S, 39. Solomon DH, Husni ME, Libby PA, Yeomans ND,
Lundberg I, Klareskog L, Alfredsson L., EIRA study Lincoff AM, Lϋscher TF, Menon V, Brennan DM,
group. Quantification of the influence of cigarette Wisniewski LM, Nissen SE, Borer JS. The Risk of
smoking on rheumatoid arthritis: results from a Major NSAID Toxicity with Celecoxib, Ibuprofen,
population-based case-control study, using incident or Naproxen: A Secondary Analysis of the
cases. Ann Rheum Dis., 2003 Sep; 62(9): 835-41. PRECISION Trial. Am J Med., 2017 Dec; 130(12):
31. Padyukov L, Silva C, Stolt P, Alfredsson L, 1415-1422.e4.
Klareskog L. A gene-environment interaction 40. van Everdingen AA, Jacobs JW, Siewertsz Van
between smoking and shared epitope genes in HLA- Reesema DR, Bijlsma JW. Low-dose prednisone
DR provides a high risk of seropositive rheumatoid therapy for patients with early active rheumatoid
arthritis. Arthritis Rheum., 2004 Oct; 50(10): arthritis: clinical efficacy, disease-modifying
3085-92. properties, and side effects: a randomized, double-
32. Linn-Rasker SP, van der Helm-van Mil AH, van blind, placebo-controlled clinical trial. Ann Intern
Gaalen FA, Kloppenburg M, de Vries RR, le Cessie Med., 2002 Jan 01; 136(1): 1-12.

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Nagaraju et al. World Journal of Pharmaceutical and Life Science

41. Bakker MF, Jacobs JW, Welsing PM, Verstappen

SM, Tekstra J, Ton E, Geurts MA, van der Werf JH,
van Albada-Kuipers GA, Jahangier-de Veen ZN, van
der Veen MJ, Verhoef CM, Lafeber FP, Bijlsma JW.,
Utrecht Rheumatoid Arthritis Cohort Study Group.
Low-dose prednisone inclusion in a methotrexate-
based, tight control strategy for early rheumatoid
arthritis: a randomized trial. Ann Intern Med., 2012
Mar 06; 156(5): 329-39.
42. Singh JA, Saag KG, Bridges SL, Akl EA, Bannuru
RR, Sullivan MC, Vaysbrot E, McNaughton C,
Osani M, Shmerling RH, Curtis JR, Furst DE, Parks
D, Kavanaugh A, O'Dell J, King C, Leong A,
Matteson EL, Schousboe JT, Drevlow B, Ginsberg
S, Grober J, St Clair EW, Tindall E, Miller AS,
McAlindon T. 2015 American College of
Rheumatology Guideline for the Treatment of
Rheumatoid Arthritis. Arthritis Rheumatol., 2016
Jan; 68(1): 1-26. [PubMed]
43. Porter D, van Melckebeke J, Dale J, Messow CM,
McConnachie A, Walker A, Munro R, McLaren J,
McRorie E, Packham J, Buckley CD, Harvie J,
Taylor P, Choy E, Pitzalis C, McInnes IB. Tumour
necrosis factor inhibition versus rituximab for
patients with rheumatoid arthritis who require
biological treatment (ORBIT): an open-label,
randomised controlled, non-inferiority, trial. Lancet,
2016 Jul 16; 388(10041): 239-47.
44. Wallenstein GV, Kanik KS, Wilkinson B, Cohen S,
Cutolo M, Fleischmann RM, Genovese MC, Gomez
Reino J, Gruben D, Kremer J, Krishnaswami S, Lee
EB, Pascual-Ramos V, Strand V, Zwillich SH.
Effects of the oral Janus kinase inhibitor tofacitinib
on patient-reported outcomes in patients with active
rheumatoid arthritis: results of two Phase 2
randomised controlled trials. Clin Exp Rheumatol.,
2016 May-Jun; 34(3): 430-42.
45. Smolen JS, Breedveld FC, Burmester GR, Bykerk V,
Dougados M, Emery P, et al. Treating rheumatoid
arthritis to target: 2014 update of the
recommendations of an international task force. Ann
Rheum Dis. 2016 Jan; 75(1): 3–15. doi:
10.1136/annrheumdis-2015-207524. [DOI] [PMC
free article] [PubMed] [Google Scholar][Ref list]
46. [Link] and Dale’s pharmacology 6th edition, Anti-
inflammatory activity of NSAIDs, 215.

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