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© 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
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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].
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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].
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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].
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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]
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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)
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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]
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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
Gastrointestinal side
effects
[34]
16 Meloxicam
Non selective COX
inhibitor
15 mg orally
daily
Gastrointestinal side
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]
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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]
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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]
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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.
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