© 2018 ijrar november 2018, volume 5, issue 4 ...ijrar.org/papers/ijrar1bnp045.pdfassociated with...

© 2018 IJRAR November 2018, Volume 5, Issue 4 www.ijrar.org (E-ISSN 2348-1269, P- ISSN 2349-5138)

IJRAR1BNP045 International Journal of Research and Analytical Reviews (IJRAR) www.ijrar.org 531

Rheumatoid arthritis: Diagnosis and Management

Harmanjot Kaur, Bhupinder Kapoor*, Reena Gupta, Mukta Gupta

School of Pharmaceutical Sciences, Lovely Professional University, Punjab 144401, India

Abstract

Rheumatoid arthritis, a persistent systemic inflammatory disorder of joints, is one of the leading cause of joint

deformity, which ultimately results in compromised quality of life. Various categories of drugs such as

nonsteroidal inflammatory drugs (NSAIDs), disease modifying anti-rheumatic drugs (DMARDS),

glucocorticoids, biologics etc. are being used for the management of disease. The present review summarizes the

current status of this disease along with the different therapeutic approaches.

Keywords: Rheumatoid arthritis; Nonsteroidal anti-inflammatory drugs; Disease modifying anti-rheumatic

drugs; Biologics

1 Rheumatoid Arthritis

1.1 Introduction

Rheumatoid arthritis (RA) is a persistent systemic inflammatory disorder which is characterized by chronic

inflammation of synovial membrane (synovitis) that leads to joint deformity and permanent loss of function in

the later on stages [1]. It affects multiple joints, including the small joints in the wrists and hands (carpals,

interphalangeal and metacarpophalangeal joints) as well as, over the time, other larger joints of the body such as

feet, shoulders, elbows, knees and ankles (subtalar joint) [2]. The progressive damage to joints leads to

impairment of the joints and loss of function. RA is one of the most frequent occurring inflammatory joint

diseases and causes premature mortality, dysfunctioning and compromised quality of life [3].

Figure 1: Healthy joint vs RA joint

http://www.ijrar.org/



1.2 Signs and symptoms [4]

RA usually shows following symptoms and they are more prominent in the morning or after long rest and lack

of exercise.

Pain areas: ankle, back, fingers, neck, in the joints, muscles, hands and wrist can be irregular, can occur

while sitting

Joints: stiffness, swelling or tenderness

Muscular: reduced range of movement, challenging walking, or muscle exhaustion

Hand: nodules formulation (rheumatoid nodules)

Whole body: fatigue or malaise, low-grade fever, loss of energy

Also common: flare, neck stiffness, loss of appetite, physical deformity, or redness

1.3 Diagnosis

Early diagnosis is considered to be the primary improvement metric for the most favorable results as well as cost

effectiveness as the first 12 weeks after early symptoms occur are considered to be the best therapeutic window.

However, early diagnosis remains difficult as the patient may be asymptomatic during this phase and require a

lot of examination and medical analysis [5]. The following tests are used for the diagnosis of RA:

1.3.1 Routine blood test

Complete blood count including liver function tests, kidney function tests and C-reactive protein (CRP) should

be performed at the initial stage of evaluation. Anemia has been also observed in some RA patients. If the liver

function tests are anomalous, it indicates concomitant disease process is present. Often serum albumin may be

weak, which is a sign of systemic inflammation going on [6].

1.3.2 Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

ESR and CRP are the two main inflammatory biomarkers in RA. In patients with active disease these markers

are typically elevated and declined with treatment. The inflammatory markers ESR and CRP markers along with

the signs of the patients, the number of swollen joints, the number of tender joints are comprised into a score

called as disease activity score (DAS) and is very useful for tracking illness occurrence over time [7].

1.3.3 Rheumatoid factor (RF)

RF are antibodies can be of any immunoglobulin subclass (IgA, IgG, and IgM) but most often IgM. RFs can be

determined in the laboratory by enzyme-linked immunosorbent assay (ELISA), or by nephelometry. The cut off

value for a positive RF varies depending on the methodology employed but a typical cutoff point exceeds 45

IU/mL ELISA. In the light of clinical results the outcome of a positive RF should be carefully interpreted. In

elderly people RF in low titers is positive, in chronic infections like hepatitis C [8].




1.3.4 Anti-citrullinated peptide antibodies (ACPA)

ACPA are protein-directed antibodies to citrullinated residues. Citrulline is an amino acid that doesn’t occur

naturally. Recombinant cyclic-shaped fillagrin protein is a particularly useful substrate for detecting these auto

antibodies. ACPA is usually detected by ELISA in laboratory. They are more specific for early RA diagnosis

than RF. Their sensitivity is 70%, and the specificity for diagnosis of proven RA approaches 96% [9].

1.3.5 Radiology

Radiological examination of joints is used to analyze the soft tissue swelling as well as joint deformity. The X-

rays of hands, wrists and feet can performed in the initial stages and is one of the important examination in the

diagnosis of RA [10].

1.4 Prevalence

The global prevalence of the disease ranges from 0.8% to 1% as per World Health Organization. The incidence

in women is reported to be three times higher as compared to men; although the reason is not clear but the

involvement of genetic factors are expected to be responsible for this. It has been documented that 50% of

patients in developed countries are unable to hold down a fulltime job after 10 years of onset of disease [11]. In

most subgroups, the incidence of arthritis among people 65 years of age and older, women, and obese individuals,

was highest. RA appears to occur between the ages of 20 and 40, during the most active years of adulthood, and

is a persistent debilitating disorder that also causes discomfort and deformation. Arthritis affects more than 180

million people in the Indian population of 15 per cent. This incidence is higher than many well-known diseases

like diabetes, AIDS and cancer [12].

1.5 Treatment

Presently, the four main classes of medications are used to treat RA are following:

1.5.1 Slow acting anti-rheumatic drugs (SAARDs)

Slow acting anti-rheumatic drugs (SAARDs), also known as disease modifying anti-rheumatic drugs (DMARDs)

as they act on underlying cause of the disease. They not only provide the symptomatic relief but also delay the

progression of disease and ultimately keeps the joints healthy for longer period of time [13]. DMARDs may take

2-4 months to show therapeutic effects in RA [14]. Even with remission of the disease, DMARD therapy should

be continued indefinitely. Chloroquine, hydroxychloroquine, sulfasalazine, methotrexate and leflunomide are

commonly used DMARDs. Some less commonly used DMARDs are gold salts, cyclosporine, D-penicillamine

and azathioprine. Tetracycline antibiotic such as doxycycline, and minocycline are used in the early stages as an

adjunctive therapy [15].




1.5.2 Non-steroidal anti-inflammatory drugs (NSAIDS)

Non-steroidal anti-inflammatory drugs (NSAIDs) don’t change the course of the disease but provide symptomatic

relief. They are rarely used along, rather used in combination with first line DMARDs such as methotrexate [16].

The target site for NSAIDs is cyclooxygenase (COX) enzymes which are responsible for generation of

inflammatory mediators. Inhibition of COX decreases the production of inflammatory mediators and reduces the

inflammation. But non-selective inhibition of both COX-1 and COX-2 are also responsible for gastrointestinal

side effects. Due to this reason, selective COX-2 inhibitors are preferred over non-selective inhibitors in

management of RA [17].

1.5.3 Glucocorticoids

Use of glucocorticoids in early RA can suppress inflammation and retard joint damage. They are given in low

dose for shorter duration that acts as bridge therapy with the calcium and Vitamin D as oral supplements for

preventing de-mineralize of the bones. They slow the rate of joint damage. When given for long duration can

cause body dependence. Prednisolone is the drug of choice for glucocorticoids [18].

1.5.4 Biologics

A biologic medication is the product that is developed from living organisms or their components. Biologics is

the latest generation of drugs that uses target cytokines, signaling molecules and cells that cause inflammation

and joint degradation [19]. It includes following:

1.5.4.1 Anti-cytokine therapies

The first biologics used for treating RA were the anti-cytokine agents. Their use is based upon greater

understanding of the RA biology. There are currently anti-TNF-α agents operating in India- infliximab and

etanercept, the IL-1receptor antagonist, IL-6 blocker tocilizumab and anakinra [20].

1.5.4.2 Other Biologic Agents

Other biologic response modifiers are abatacept and the monoclonal antibody depleting B-cell, rituximab. Most

biologics bear an increased risk of opportunistic infections, though successful [21].




Table 1: Therapeutic agents used in the treatment of RA

S.No Drug name Chemical structure Molecular target Dose Side effects Reference

Disease modifying anti-rheumatoid drugs (DMARDs)

1 Sulphasalazine

Cytokines

(interleukin and

tumor necrosis

factor)

500 mg od Oligospermia,

gastrointestinal

discomfort, discoloration

of body fluids, weight

loss, nausea, vomiting

[22]

2 Methotrexate

Cytokines

(interleukin and

tumor necrosis

factor)

7.5 to 10 mg

once weekly

Pulmonary toxicity, bone

marrow and liver

toxicity, stomatitis and

ulcers

[23]

3 Leflunomide

Pyrimidine

synthesis

inhibitor

10-20 mg od Teratogenicity, liver

toxicity, alopecia, rash,

dyspepsia, delayed

menses, nausea,

vomiting

[24]

4 Hydroxychloroquine

Immunomodulatory

effects

200-400 mg od Retinal toxicity,

headache, abdominal

pain, allergic reactions,

nausea, vomiting

[25]




5 Azathioprine

Cytokines

(interleukin and

tumor necrosis

factor)

50-100 mg od gastrointestinal

symptoms, leucopenia, hepatotoxicity and

pancreatitis

[26]

6 Minocycline

Cytokines

(interleukin and

tumor necrosis

factor)

100 mg twice

daily

Nausea, diarrhea, rash,

photosensitivity

reactions, dizziness,

headache, fingernail

discoloration, increased

appetite, and change in

taste

[27]

7 Cyclosporine

Cytokines

(interleukin and

tumor necrosis

factor)

5-10 mg/kg High blood pressure,

kidney problems, nausea,

vomiting, abdominal

pain, tremors, increased

hair growth, gum

swelling, muscle cramps,

or numbness and tingling

of the hands or feet

[28]

8 Aurothiomalate

Cytokines

(interleukin and

tumor necrosis

factor)

50 mg weekly Dyspepsia, mouth

swelling, nausea,

vomiting and taste

disturbance

[29]

Non- Steroidal anti-inflammatory drugs (NSAIDs)




9 Etoricoxib

COX-2 inhibitor 90 mg od Indigestion, stomach

upset, gastrointestinal

and cardiovascular risk

factor.

[27]

10 Celecoxib

COX-2 inhibitor 90-200 mg od Flu like symptoms,

peripheral edema,

flatulence, indigestion,

gastrointestinal and

cardiovascular risk

factor.

[30]

11 Diclofenac

Non-selective COX

inhibitor

50-100 mg od Heartburn, epigastric

pain, indigestion,

vomiting.

[3]

12 Ketoprofen

Non selective COX

inhibitor

50-200 mg od Vomiting, indigestion,

nausea.

[31]

13 Ibuprofen

Non selective COX

inhibitor

1200 mg/day Gastrointestinal side

effects

[32]




14 Naproxen

Non selective COX

inhibitor

250-500 mg

orally twice a

day

Gastrointestinal side

effects

[33]

15 Indomethacin

Non selective COX

inhibitor

25 mg twice a

day


effects

[34]

16 Meloxicam

Non selective COX

inhibitor

15 mg orally

daily


effects

[35]

Glucocorticoids

17 Prednisolone

Corticosteroid

hormone receptor

agonist

Less than 10-15

mg od

Skin thinning, decreased

bone density, increased

infection risk, behavioral

changes.

[36]

18 Dexamethasone

Corticosteroid

hormone receptor

agonist

0.75-9 mg od. Mood changes,

decreased bone density,

stomach upset, allergic

reactions.

[36]




19 betamethasone

Corticosteroid

hormone receptor

agonist

0.6 mg – 1 mg

equivalent dose

od

Skin thinning, decrease

in bone density, sudden

withdrawal cause mood

changes.

[36]

20 Methylprednisolone

Corticosteroid

hormone receptor

agonist

80-120 mg,

intramuscularly,

every 4 weeks

for the first 2-4

months

Stomach upset, weight

gain, reduction in bone

density, increased risk of

infection, behavioral

changes.

[36]

21 Hydrocortisone

Corticosteroid

hormone receptor

agonist

20 mg daily Stomach upset, weight

gain, reduction in bone

density, increased risk of

infection, behavioral

changes.

[36]

Biologics

22 Adalimumab

-

TNF-α inhibitor 40 mg / 0.8 ml

Subcutaneously

every 2 weeks

Sinus inflammation,

hypertension,,rash, upper

respiratory tract

infection, headache.

[20]

23 Abatacept

-

T-cell costimulation

blocker

500–1000 mg

IV every 4

weeks

Nasopharyngitis, upper

respiratory tract

infection, malignancy.

nausea, headache.

[20]




24 Golimumab

-

TNF-α inhibitor 50 mg once a

month

subcutaneously

Severe /anaphylactoid

transfusion reaction

[20]

25 Anakinra

-

IL-1 inhibitor 100 mg od

subcutaneously

Injection site reactions,

infections, neutropenia,

malignancy

[20]


© 2018 IJRAR November 2018, Volume 5, Issue 4 www.ijrar.org (E-ISSN 2348-1269, P-

ISSN 2349-5138)


3. Conclusion

Rheumatoid arthritis is common persistent, systemic autoimmune disease which predominantly

affects the joints. It cause inflammation, bone erosion and in severe cases complete joint

destruction. Despite various advancements in research of RA, neither single drug nor combination

therapy has acquired promising results. With the advent of various drugs new targets have been

approached.

4. References

[1] J. K. Amaral, J. B. Bilsborrow, and R. T. Schoen, “Chronic Chikungunya Arthritis and

Rheumatoid Arthritis: What They Have in Common,” The American Journal of Medicine,

vol. 133, no. 3, pp. e91-e97, 2020.

[2] B. Kapoor, S. K. Singh, M. Gulati, R. Gupta, and Y. Vaidya, “Application of liposomes in

treatment of rheumatoid arthritis: quo vadis,” ScientificWorldJournal, vol. 2014, pp.

978351. 2014.

[3] S. Thakur, B. Riyaz, A. Patil, A. Kaur, B. Kapoor, and V. Mishra, “Novel drug delivery

systems for NSAIDs in management of rheumatoid arthritis: An overview,” Biomedicine

& Pharmacotherapy, vol. 106, pp. 1011-1023, 2018.

[4] G. S. Jutley, Z. P. Latif, and K. Raza, “Symptoms in individuals at risk of rheumatoid

arthritis,” Best Practice & Research Clinical Rheumatology, vol. 31, no. 1, pp. 59-70, 2017.

[5] H. Allard-Chamard, and G. Boire, “Serologic Diagnosis of Rheumatoid Arthritis,” Clinics

in Laboratory Medicine, vol. 39, no. 4, pp. 525-537, 2019.

[6] E. A. Littlejohn, and S. U. Monrad, “Early Diagnosis and Treatment of Rheumatoid

Arthritis,” Primary Care: Clinics in Office Practice, vol. 45, no. 2, pp. 237-255, 2018.

[7] M. A. D'Agostino, E. A. Haavardsholm, and C. J. van der Laken, “Diagnosis and

management of rheumatoid arthritis; What is the current role of established and new

imaging techniques in clinical practice?,” Best Practice & Research Clinical

Rheumatology, vol. 30, no. 4, pp. 586-607, 2016.



ISSN 2349-5138)


[8] A. Tedesco, D. D'Agostino, I. Soriente, P. Amato, R. Piccoli, and P. Sabatini, “A new

strategy for the early diagnosis of rheumatoid arthritis: A combined approach,”

Autoimmunity Reviews, vol. 8, no. 3, pp. 233-237, 2009.

[9] B. Vander Cruyssen, I. Peene, T. Cantaert, I. E. A. Hoffman, L. De Rycke, E. M. Veys,

and F. De Keyser, “Anti-citrullinated protein/peptide antibodies (ACPA) in rheumatoid

arthritis: Specificity and relation with rheumatoid factor,” Autoimmunity Reviews, vol. 4,

no. 7, pp. 468-474, 2005.

[10] E. Llopis, H. M. Kroon, J. Acosta, and J. L. Bloem, “Conventional Radiology in

Rheumatoid Arthritis,” Radiologic Clinics of North America, vol. 55, no. 5, pp. 917-941,

2017.

[11] T. Otón, and L. Carmona, “The epidemiology of established rheumatoid arthritis,” Best

Practice & Research Clinical Rheumatology, pp. 101477, 2020.

[12] P. Conigliaro, P. Triggianese, E. De Martino, G. L. Fonti, M. S. Chimenti, F. Sunzini, A.

Viola, C. Canofari, and R. Perricone, “Challenges in the treatment of Rheumatoid

Arthritis,” Autoimmunity Reviews, vol. 18, no. 7, pp. 706-713, 2019.

[13] V. K. Ranganath, and D. E. Furst, “Disease-modifying antirheumatic drug use in the elderly

rheumatoid arthritis patient,” Rheumatic Disease Clinics of North America, vol. 33, no. 1,

pp. 197-217, 2007.

[14] L. D. Quan, G. M. Thiele, J. Tian, and D. Wang, “The Development of Novel Therapies

for Rheumatoid Arthritis,” Expert Opin Ther Pat, vol. 18, no. 7, pp. 723-738, 2008.

[15] M. M. Bonafede, K. M. Fox, B. H. Johnson, C. Watson, and S. R. Gandra, “Factors

associated with the initiation of disease-modifying antirheumatic drugs in newly diagnosed

rheumatoid arthritis: a retrospective claims database study,” Clin Ther, vol. 34, no. 2, pp.

457-67, 2012.

[16] T. J. Atkinson, and J. Fudin, “Nonsteroidal Antiinflammatory Drugs for Acute and Chronic

Pain,” Physical Medicine and Rehabilitation Clinics of North America, 2020.

[17] T. J. Schnitzer, K. Truitt, R. Fleischmann, P. Dalgin, J. Block, Q. Zeng, J. Bolognese, B.

Seidenberg, and E. W. Ehrich, “The safety profile, tolerability, and effective dose range of



ISSN 2349-5138)


rofecoxib in the treatment of rheumatoid arthritis. Phase II Rofecoxib Rheumatoid Arthritis

Study Group,” Clin Ther, vol. 21, no. 10, pp. 1688-702, 1999.

[18] C. B. Kahn, J. L. Hollander, and H. R. Schumacher, “Corticosteroid crystals in synovial

fluid,” Jama, vol. 211, no. 5, pp. 807-9, 1970.

[19] R. Davies, and K. L. Hyrich, “Biologics registers in rheumatoid arthritis,” Medicine, vol.

46, no. 4, pp. 243-246, 2018.

[20] S. T. Law, and P. C. Taylor, “Role of biological agents in treatment of rheumatoid

arthritis,” Pharmacological Research, vol. 150, pp. 104497, 2019.

[21] S. J. Girdler, I. Ye, R. Tang, and N. Kirschner, “Altering the natural history of rheumatoid

arthritis: The role of immunotherapy and biologics in orthopaedic care,” Journal of

Orthopaedics, vol. 17, pp. 17-21, 2020.

[22] G. L. Plosker, and K. F. Croom, “Sulfasalazine,” Drugs, vol. 65, no. 13, pp. 1825-1849,

2005.

[23] O. Al‐Khalili, T. R. Mikuls, J. R. O'Dell, and B. R. England, “Methotrexate and NSAID s

in rheumatoid arthritis—C onfirmation of a known NSAID s adverse effect rather than a

dangerous combination,” Pharmacoepidemiology and drug safety, vol. 27, no. 12, pp.

1429-1429, 2018.

[24] M. L. Herrmann, R. Schleyerbach, and B. J. Kirschbaum, “Leflunomide: an

immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune

diseases,” Immunopharmacology, vol. 47, no. 2-3, pp. 273-89, 2000.

[25] E. R. Bendas, H. Abdullah, M. H. El-Komy, and M. A. Kassem, “Hydroxychloroquine

niosomes: a new trend in topical management of oral lichen planus,” Int J Pharm, vol. 458,

no. 2, pp. 287-95, 2013.

[26] E. C. Van Os, B. J. Zins, W. J. Sandborn, D. C. Mays, W. J. Tremaine, D. W. Mahoney,

A. R. Zinsmeister, and J. J. Lipsky, “Azathioprine pharmacokinetics after intravenous, oral,

delayed release oral and rectal foam administration,” Gut, vol. 39, no. 1, pp. 63-8, 1996.



ISSN 2349-5138)


[27] A. Syed, and V. K. Devi, “Potential of targeted drug delivery systems in treatment of

rheumatoid arthritis,” Journal of Drug Delivery Science and Technology, vol. 53, pp. 2019.

[28] E. Zampeli, P. G. Vlachoyiannopoulos, and A. G. Tzioufas, “Treatment of rheumatoid

arthritis: unraveling the conundrum,” Journal of autoimmunity, vol. 65, pp. 1-18, 2015.

[29] P. J. Konigsberg, J. E. Debrick, T. J. Pawlowski, and U. D. Staerz, “Liposome encapsulated

aurothiomalate reduces collagen-induced arthritis in DBA/1J mice,” Biochim Biophys

Acta, vol. 1421, no. 1, pp. 149-62, 1999.

[30] A. Deniz, A. Sade, F. Severcan, D. Keskin, A. Tezcaner, and S. Banerjee, “Celecoxib-

loaded liposomes: effect of cholesterol on encapsulation and in vitro release

characteristics,” Biosci Rep, vol. 30, no. 5, pp. 365-73, 2010.

[31] J. Wang, S.-q. Zhao, M.-y. Zhang, and B.-s. He, “Targeted eco-pharmacovigilance for

ketoprofen in the environment: Need, strategy and challenge,” Chemosphere, vol. 194, pp.

450-462, 2018.

[32] E. H. Giannini, E. J. Brewer, M. L. Miller, D. Gibbas, M. H. Passo, H. M. Hoyeraal, B.

Bernstein, D. A. Person, C. W. Fink, L. A. Sawyer, and M. L. Scheinbaum, “Ibuprofen

suspension in the treatment 1990.

[33] C. Bombardier, L. Laine, A. Reicin, D. Shapiro, R. Burgos-Vargas, B. Davis, R. Day, M.

B. Ferraz, C. J. Hawkey, and M. C. Hochberg, “Comparison of upper gastrointestinal

toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis,” New England

Journal of Medicine, vol. 343, no. 21, pp. 1520-1528, 2000.

[34] N. Baber, L. Halliday, W. Van Den Heuvel, R. Walker, R. Sibeon, J. Keenan, T. Littler,

and M. E. Orme, “Indomethacin in rheumatoid arthritis: clinical effects, pharmacokinetics,

and platelet studies in responders and nonresponders,” Annals of the rheumatic diseases,

vol. 38, no. 2, pp. 128-136, 1979.

[35] S. Noble, and J. A. Balfour, “Meloxicam,” Drugs, vol. 51, no. 3, pp. 424-30; discussion

431-32, 1996.

[36] J. F. Ferreira, A. A. Ahmed Mohamed, and P. Emery, “Glucocorticoids and Rheumatoid

Arthritis,” Rheumatic Disease Clinics of North America, vol. 42, no. 1, pp. 33-46, 2016.


© 2018 ijrar november 2018, volume 5, issue 4 ...ijrar.org/papers/ijrar1bnp045.pdfassociated with...

Documents