Rheumatoid Arthritis

Abera J. (B.Pharm, MSc in Clinical Pharmacy).

07/08/2022 By; Abera J 1

 Learning Objectives

• Upon completion of the chapter, the student will be able to:

– Identify RFs for developing RA,

– Describe the pathophysiology of RA,

– Discuss the comorbidities associated with RA,

– Recognize the typical clinical presentation of RA,

– Recommend appropriate treatments,

– Formulate a monitoring plan to evaluate the safety and efficacy

of a therapeutic regimen

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 RA...
• RA is a chronic, progressive autoimmune disorder
– In response to an unknown trigger, the body makes
antibodies that attack its own tissues
– The self-attacks mostly affect the joints, although they can
also affect other body parts
– Disease attacks, called flare-ups, occur periodically, or can
be continuous in some people
• RA is a chronic disorder; hence, early, aggressive treatment
is key to slowing or stopping its progression

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 RA...
• What is it?

– Chronic: long-term disease, no cure

– Inflammatory: causes swelling of joints

– Autoimmune: body recognizes self as foreign

substance
– Systemic: can affect other organs

– Symmetrical: affects opposite joints equally

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 RA...

• Who gets it?

– RA is more prevalent in women and more severe in

men and old people

– 70% of Pt.s are women

– Men are more severely affected

– Onset between 30 and 50 years old

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 Juvenile RA (JRA)
• JRA……is the most common form of arthritis in children.

• Like adult RA, it causes

– joint inflammation, stiffness, and damage

– However, it can also affect a child's growth

• JRA is also known as juvenile idiopathic arthritis

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 Pathophysiology
• The pathogenesis of RA is driven by T lymphocytes,
– but the initial catalyst causing this response is
unknown.
• The components of most significance are;
– T lymphocytes, cytokines, B lymphocytes, and
kinases

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 Pathophysiology…

• Activation of mature T lymphocytes requires two

signals.
– The first is the presentation of an antigen by antigen
presenting cells to the T-lymphocyte receptor.
– Second, a ligand receptor complex on antigen-
presenting cells binds to CD28 receptors on T
lymphocytes.

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 Pathophysiology…
• Once a cell successfully passes through both stages, the
inflammatory cascade is activated.
• Activation of T lymphocytes:
– Stimulates the release of macrophages or monocytes, which
subsequently causes the release of inflammatory cytokines;
– Activates osteoclasts;
– Activates release of enzymes which responsible for the
degradation of connective tissue; and
– Stimulates B lymphocytes and the production of antibodies

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 Pathophysiology…
Cytokines
• Cytokines are proteins secreted by cells that serve as
intercellular mediators
• An imbalance of proinflammatory and anti-
inflammatory cytokines in the synovial leads to
inflammation and joint destruction.

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 Pathophysiology…

• Proinflammatory cytokines cause activation of other

cytokines and adhesion molecules responsible for
recruitment of lymphocytes to the site of inflammation
• Anti-inflammatory cytokines and mediators are present in
the synovium,
– Although concentrations are not high enough to overcome
the effects of the proinflammatory cytokines.

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 Pathophysiology…
B-Lymphocytes
• B-lymphocytes may produce proinflammatory cytokines and antibodies.
• Antibodies of significance in RA are RF and anticitrullinated protein
antibodies (ACPA).
• RFs are not present in all Pt.’s with RA,
– But, their presence is indicative of disease severity and structural
progression.

• ACPA are produced early in the course of disease;

– High levels of ACPA are indicative of aggressive disease and a greater
likelihood of poor outcomes.

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 Cytokines Involved in the Pathogenesis of RA

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 Comorbidities Associated with RA
• RA reduces a Pt.’s average life expectancy, but RA alone rarely
causes death.
• Instead, specific comorbidities contribute to premature death,

– The comorbidities with the greatest impact on morbidity

and mortality associated with RA are;
– CV disease,

– Infections,

– Malignancy, and

– Osteoporosis

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 Comorbidities Associated with RA…
CV Disease
• More than half of all deaths in RA Pt.’s are CV related.
• Because a Pt.’ with RA experiences inflammation and
swelling in joints,
– it is likely that there is inflammation elsewhere, such as
in the blood vessels, termed vasculitis.
• CRP, a nonspecific marker of inflammation,
– It is associated with an increased risk of CV disease;

• CRP is elevated in Pt.’s with RA.

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 Comorbidities Associated with RA…
Infections
• Pt.’s with RA have an increased risk of infections;

– Older age, disease activity, and concomitant conditions

(ie, renal failure, lung disease) may increase risk of
infection.
– Additionally, prolonged glucocorticoid use may contribute
to infection risk.
– Pt.’s and clinicians must pay close attention to signs and
symptoms of infection.

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 Comorbidities Associated with RA…
Malignancy
• CA is the second most common cause of death in RA Pt.’s.
– There is an overall increased risk of lymphoma, leukemia,
multiple myeloma, melanoma, and lung CA
– But decreased risk of developing CA of the cervix,
prostate, and digestive tract ????
– Research is underway to understand the
mechanisms that increase or decrease risk of
specific CAs

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 Comorbidities Associated with RA…
Osteoporosis
– Cytokines involved in the inflammatory process directly
stimulate osteoclast and inhibit osteoblast activity.

– Additionally, arthritis medications can lead to

increased bone loss.
– BMD should be evaluated at baseline and
routinely using DXA

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 Clinical presentation of RA

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Diagnosing RA

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 Comparison of RA and Osteoarthritis

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 Goals of Therapy

• The short-term goal of treatment is;

– To reduce joint pain and swelling and
– To maintain and/or improve joint function
• The long-term goal of treatment is;
– To slow or stop the disease process,
– Control systemic complications, and
– Improve/maintain QoL.

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 Treatment of RA
• There is no known cure for RA
– Aggressive treatment should be started as early as
possible
– Treatment includes a combination of medication and
exercises to strengthen supporting muscles around the
joints
• Treatment is tailored to the individual, taking into account
their age, affected joints, and the progression of the
disease

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 Treatment of RA…

Bridge Therapy/Symptomatic Relief

• The current standard of care for RA treatment is to initiate
disease-modifying therapy immediately.
• While this step is critical to control the underlying disease
activity,
– it may take weeks to months for the Pt to experience relief.
• It is acceptable to initiate “bridge therapy” or short-term
use of certain medications to provide symptomatic relief
• NSAIDs and glucocorticoids are the most commonly
used drugs for this purpose
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 Treatment of RA…
• Medications used to treat RA include;
– Disease-modifying antirheumatic drugs (DMARDs)
– Biologics,

– NSAIDs, Steroids, and

– Other pain relievers
• DMARDs slow progression of disease and are usually used with
NSAIDs and Steroids in most treatments

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 NSAIDs

• These agents provide analgesic and anti-inflammatory

benefits for joint pain and swelling.
• However, they do not prevent joint damage or change the
underlying disease.
– Examples:
• Ibuprofen
• Naproxen
• Aspirin

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 NSAID: Aspirin
• Side Effects
– Stomach upset
– Heartburn
– Allergy
– Ringing in the ears
– Swelling
– Trouble breathing
– Itching
– Black stools . . . due to bleeding of upper GI?

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 Steroids
Glucocorticoids
• Effectively reduces inflammation through inhibition of
cytokines and inflammatory mediators,
• Prevents disease progression.
• Example
• Prednisone
– Take with food to avoid upset of stomach
– Take pill in the morning to avoid insomnia
– May increase glucose levels
– Do not discontinue abruptly vs. adrenal insufficiency

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 Steroids…
• Who should not take Steroids?
– Steroids are not recommended for everyone
– In general, people with the following conditions should
not take steroids:
• Infection . . . Immunosuppression
• Uncontrolled DM. . . hyperglycemia
• Uncontrolled high BP or CHF . . . HTN, Sodium and
water retention
• Peptic ulcer . . . GI ulceration or aggravation
• Osteoporosis (bone thinning)
• Glaucoma

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 Steroids…

– Reduce the dose gradually as long as the disease

remains under control

– Monitor BP often and treat if necessary

– Use calcium supplements and bisphosphonates,

to help maintain bone density

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 Steroids: Side Effects
• SEs are much more common with oral drugs and are dose related
– Acne
– Blurred vision, or glaucoma – Risk of infection
– Muscle weakness,
– Easy bruising
Nervousness, restlessness
– Difficulty sleeping (insomnia) – Stomach irritation or
– High blood pressure bleeding
– Sudden mood swings
– Increased appetite, weight gain – Swollen, puffy face
– Increased growth of body hair – Water retention, swelling
– – Worsening of DM
Osteoporosis

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 Treatment of RA…
• Disease-Modifying Anti-Rheumatic Drugs (DMARDs)
– Slow joint destruction
– Examples
• Methotrexate (Rheumatrex)
• Leflunomide (Arava)
• Hydroxychloroquine (Plaquenil)
• Azathioprine (Imuran)
• Sulfasalazine (Azulfidine)
• Minocycline (Minocin)
• Cyclosporine (Neoral )

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 DMARDs…
• Methotrexate (MTX)
– Most commonly used
– Inhibit of dihydrofolate reductase, which causes inhibition
of purines and thymidylic acid,
– Also inhibit production of certain cytokines
– Safe and easy to use, even in children
• Dose: 7.5 mg PO weekly
• S/E: can cause stomach upset, toxic to the liver or BM, as
well as birth defects, SOB-rare cases
– Regular blood work is necessary when taking
methotrexate
– Taking folic acid helps reduce some of the SEs

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 DMARDs…
• Hydroxychloroquine and sulfasalazine
– Used for mild rheumatoid arthritis
• Not as powerful as other DMARDs,
• Hydroxychloroquine is not associated with renal, hepatic, or
BM suppression
– Therefore, may be an acceptable treatment option for
Pt.s with CI to other DMARDs
– In rare cases, Hydroxychloroquine can adversely affect the eyes,
• Pt.’s taking this medicine should be seen by an
ophthalmologist at least once a year

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 DMARDs…
• Minocycline
– A TTC antibiotic
– May help RA by stopping inflammation
– It can take several months to start working and up to a
year before the full effects are known
– When taken for long periods, minocycline can cause
discoloration of the skin
– Discolors teeth in children and affects bones
– Do not use in pregnancy
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 DMARDs…

• Leflunomide
– Works similar to MTX and can work even better in
combination with it
– SEs are similar to MTX
– Sometimes it causes diarrhea
– Since Leflunomide is known to cause harm to a fetus,
– Women must take special precautions to not get
pregnant while on it

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 DMARDs…
• Cyclosporine
– A powerful drug that often works well in slowing down joint
damage
– Reserved for severe RA owing to its ability to cause
nephrotoxicity, HTN, and hyperlipidemia
• Azathioprine
– Used for many inflammatory conditions, including RA
– Most common SEs are N/V, sometimes with stomach pain and
diarrhea
– Long-term use of azathioprine is associated with an increased
risk of CA
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 Biological Response Modifiers
• Target the body’s immune system
– Biologics have been shown to help slow progression of
RA when all other treatments failed
• These agents may be;
– Added to non-biologic DMARD monotherapy (eg, MTX),
– Replace ineffective non-biologic DMARD therapy, or

– Even be considered for initial therapy

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 Biological Response Modifiers
• TNF Antagonists
– Etanercept, adalimumab, infliximab, golimumab, and
certolizumab.
• IL-1 Antagonists: Anakinra and Canakinumab
• Costimulation Modulators: Abatacept
• Anti-CD20 Monoclonal Antibody: Rituximab
• IL-6 Antagonists: Tocilizumab and Sarilumab
• Janus-Kinase (JAK) Inhibitors: Tofacitinib and Baricitinib

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 Biological modifiers…

• SEs
– The most common SE seen with biologics is pain and rash
at the injection site.
• This occurs in less than 30% of Pt.’s

– May be prone to developing infections

– Vaccinations that prevent infections should be considered
prior to administration of biologics.
– Pt.’s should not receive live vaccines while taking biologic
medications

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 Biologics…
 Biologics are commonly discontinued
prior to surgery until wounds have
healed and infection risk has passed
 Pregnant women should receive
these drugs only if clearly needed
because the effects on a developing
child are unknown
 Biologics may also cause some chronic
diseases that are dormant (TB) to flare.
 Not recommended for MS & CHF.
 One disadvantage to current
biologic medications is that they
must be given either by injection
or by IV infusion.
 As a general rule, different biologic
therapies should not be taken at
the same time.
 Biologics are also more expensive
than traditional treatments.
 All Pt.’s should be skin tested for
TB prior to starting biologics
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 Is surgery an option?
• After significant joint damage has occurred or when pain or
disability becomes unbearable,
– Some people choose surgery to improve function and relieve pain

• Joint replacement is the most frequently performed surgery

for RA Pt.’s
• Other types of surgery, such as arthroscopy (inserting a tube-
like instrument into the joint to see and repair abnormal
tissues) and tendon reconstruction, can be performed as well

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 Rheumatoid Arthritis….Self-Management
• Exercise • Diet
– Flexibility – low in saturated fat
– strengthening – high in omega-3-fatty
– cardiovascular acids

• Alternative Therapy • salmon

– acupuncture • tuna

– acupressure • walnuts

– massage • canola oil

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THANK YOU.

07/08/2022 By; Abera J 44