NSAIDs SGD

Facilitator: Dr. Anita Q. Sangalang

Subsection: C6

Case:
G.G. is a 48-year-old mother. Seven months ago, she began noticing stiffness in both hands in the morning that lasted
longer and longer. Stiffness now lasted more than 1 hour every morning and included hands, wrists, and ankles. She also
had increasing difficulty standing for long periods at work or at home due to foot and ankle pain. She began taking
ibuprofen 800mg 3 times daily and found it helped her get through her day with less pain and stiffness.

Two months ago, ibuprofen was no longer very effective for her pain or stiffness. She also began feeling extremely tired
and short-tempered. She had no energy to do her usual activities. She decided that it is time to seek a consultation with
her Primary Care Physician.

A thorough physical examination was conducted, including an examination of all of Joy’s joints, many of which were
tender and swollen. Preliminary blood tests revealed positive rheumatoid factor, CCP antibodies, elevated ESR, and
C-reactive protein.

1. What is the most likely diagnosis?

Rheumatoid arthritis (RA)

- is a chronic, progressive, and disabling autoimmune disease. It causes inflammation, swelling, and pain in
and around the joints and can affect other parts of the body. It occurs on both sides of the body (symmetric).
- "began noticing stiffness in both hands in the morning that lasted longer and longeDu : During the night, your
body releases anti-inflammatory chemicals to calm joint pain and stiffness. By morning, they're no longer able
to fight the chemicals that cause inflammation, so you wake up with stiff, painful joints.
- 48 y/o = RA is among the most common inflammatory disease in older age groups (most of the time starts at
65 y/o)
- Rheumatoid factors are proteins produced by your immune system that can attack healthy tissue in your body.
High levels of rheumatoid factor in the blood are most often associated with autoimmune diseases, such as
rheumatoid arthritis and Sjogren's syndrome
- CCP (Cyclic Citrullinated Peptide) are autoantibodies, they are characteristic for diagnosing rheumatoid
Arthritis
- Positive erythrocyte sedimentation rate & CRP = indicates inflammation

2. Discuss the pathophysiology of the disease.

● Rheumatoid arthritis is one of the more common autoimmune disorders, but there is no known exact cause for
this disorder.
● RA is usually characterized with the synovium stratum, or the inner lining of the joints, to have inflammatory
processes. This eventually leads to degradation of cartilage and bone, leading to the patient experiencing pain
and also disability. Any joint lined by a synovial membrane may be involved, and extra-articular involvement of
different organs such as the skin, lungs, eyes, and heart can be significant. A patient’s existing comorbidities
can play a major role in the manifestation of a systemic inflammation
● Pathophysiology
○ Genetics and Environmental Triggers
○ Macrophages & dendritic cells are thought to present instigating antigens to T-cells, leading to T-cell
activation and proliferation
■ Many antigen targets are suspected, but they are inconsistent between different patients, so
none have been confirmed
○ The activated T-cells then produce inflammatory cytokines and stimulate B-cell differentiation into
plasma cells, leading to a systemic inflammatory response
○ DECREASED production of hyaluronan, inflammation increasing the matrix metalloproteinase
production (MMP) and INCREASED cartilage damage, immune complexes formed by plasma cell
 antibodies indirectly damages the cartilage
■ Hyaluronan is a major lubricant in synovial fluid
○ Joint damage would recruit neutrophils, T-cells & B-cells into the joint space, causing hyperplasia and
angiogenesis of the synovial membrane
■ This leads to synovial enlargement and forming palpable lumps in the joint(s), manifesting as
large, “boggy” joints
○ Neo-vascularized, hyperplastic synovium (pannus) invades and enzymatically destroys the joint tissue
(ligaments, cartilage and subchondral bone)
■ Physical narrowing of joint space decreased the joint mobility, resulting in joint stiffness and a
decrease in range of movement
○ Untreated RA will affect the entire body, resulting in the patient experiencing chronic pain, more severe
disability, and extended systemic inflammation would lead to permanent damage. Hence, we need to
take note of the importance of early detection of RA so that effective management can be initiated as
soon as possible and before the different pathological changes become irreversible.
● Differential: Arthritis caused by gout
○ RA: Autoimmune disorder
○ Gout Arthritis: Inflammatory disorder, but without an autoimmune condition.
■ High uric acid levels cause urate formation (uric acid crystals). The big toe is usually the target
of crystal formation due to its distance from the heart, because body temperature at the toes is
cooler compared to the rest of the body.

3. Identify the basic problem(s).

● Pain
● Tenderness and swollen joints
● Extremely tired
● Short-tempered
● (+) for RF and CCP
● Elevated ESR and C-reactive proteins

4. Set therapeutic goals

● Stiffness in both hands, wrists, and ankles

○ To reduce inflammation in the joints and prevent further joint damage
● Feeling extremely tired and short-tempered
○ Patients with rheumatoid arthritis typically have several inflamed joints which can lead to general
weakness, drowsiness, and exhaustion. The feeling of extreme exhaustion is often referred to as
fatigue.
○ To reduce tiredness and short-temperedness
● No energy to do usual activities
○ To relieve feelings of fatigue and weakness
● Blood tests
○ Take note of rheumatoid factor, CCP antibodies, ESR, C-reactive protein

● The therapeutic goals for Rheumatoid Arthritis include:

○ Pain or symptom relief
○ Slowing or prevention of additional joint damage
○ Stop inflammation or reduce it to the lowest possible level (put disease in remission)
○ Maintaining current levels of function and overall well-being.
○ Reduce long-term complications
○ To meet therapeutic goals:
■ Early aggressive treatment: to reduce or stop inflammation as soon as possible
■ Targeting remission or another goal
■ Tight control to keep inflammation as low as possible
 5. Plan the management.
Pharmacologic (drugs to be considered the choose the drug of choice using ESSC criteria)
Do a drug history of the patient to note any possible drug interactions
Non-pharmacologic

1. Efficacy Criteria
Efficacy Grading:
Grade the efficacy (single or drug combination:
++++ meets all the criteria
+++ meets 75% of the criteria
++ meets 50% of the criteria
+ meets 25% of the criteria

Table of Efficacy Grading:

Drug Choices Metabolism Immunosuppression Inhibition of nucleotide synthesis Grade
Methotrexate + + + +++
Tocilizumab + + / ++
Prednisone + + / ++

MECHANISM OF ACTIONS AND METABOLISM

Methotrexate MECHANISM OF ACTION
● Inhibits enzymes that are responsible for nucleotide synthesis thus preventing cell division
(e.g. dihydrofolate reductase, thymidylate synthase, aminoimidazole carboxamide
ribonucleotide transformylase (AICART), and amidophosphoribosyltransferase)

METABOLISM
● Low doses = No metabolism
● High doses undergoes hepatic and intracellular metabolism to polyglutamated forms and can
be converted back to methotrexate by hydrolase enzymes
Tocilizumab MECHANISM OF ACTION
● Prevents IL-6 mediated inflammation
● Interleukin 6 (IL-6) is a pro-inflammatory cytokine that induces antibody production, cytotoxic
T-cell differentiation and inhibits T-cell regulatory T-cell differentiation
● This binds soluble and membrane bound IL-6 receptors

METABOLISM
● Just like other monoclonal antibodies it is expected to be metabolized to smaller proteins and
amino acids by proteolytic enzymes
Prednisone MECHANISM OF ACTION
● Inhibits neutrophil apoptosis and demargination
● Inhibits phospholipase A2 → decrease formation of arachidonic acid derivatives
● Inhibit NF-Kappa B and other inflammatory transcription factors
● Promotes anti-inflammatory genes like IL-10

METABOLISM
● Metabolites and glucuronide conjugates are excreted predominantly in the urine.

2. Safety Criteria
Safety Grading:
++++ has minor tolerable side effects, ceases when the drug is discontinued
+++ significant adverse effects that require intervention but not requiring hospitalization
++ side effect requires hospitalization
+ potentially life-threatening and can result in death

Table of Safety Grading

Drug Choices ADR Safety Grading
Methotrexate ● Acute renal failure ++ (side effect requires
 ● Bone marrow suppression hospitalization)
● Nausea and mucosal ulcers
● Dose-related hepatotoxicity
● Pseudolymphomatous reactions
● Gastrointestinal toxicity
● Contraindicated in pregnancy
● Menstrual dysfunction
● Uric acid neuropathy (increase in uric acid
production)
● Pulmonary alveolar hemorrhage
● Tumor lysis syndrome
● Convulsions
Tocilizumab ● Gastrointestinal perforation +++ (significant adverse effects that
● Tuberculosis require intervention but not
● Fungal, viral, opportunistic infections requiring hospitalization)
● Upper respiratory tract infections
● Headache
● Hypertension
● Elevated liver enzymes (hepatic transaminases)
● Neutropenia, thrombocytopenia
● Increased total cholesterol, triglycerides, LDL,
HDL
● Anaphylactic reactions
Prednisone ● Adrenal suppression + (potentially life-threatening and
● Left ventricular free wall rupture can result in death)
● Visual disturbances
● Corneal perforation
● Osteoporosis
● Growth suppression in children
● Kaposi sarcoma
● Acute myopathy
● Immunosuppression
● Convulsions
● Psychiatric disturbances
● Withdrawal symptoms

3. Suitability Criteria:
Criteria
1) Less dosing frequency
a) Since the patient is middle-aged(48 years old) hence, drug clearance is decreased
2) Effective for pain and stiffness
3) Available in oral form
4) Available in the Philippines

Suitability Grading:
++++ Has beneficial effect on comorbid conditions; ideal for the patient's profile and disease
+++ not known to adversely affect comorbid conditions
++ meets 50% of set goals
+ barely meets any criterion
0 the drug is contraindicated

Table of Suitability Grading:

Drug Choices Less dosing Effective for Available in oral Available in the Grade
frequency pain and form Philippines
stiffness
 Methotrexate + + + + ++++
Tocilizumab + + / / ++
Prednisone / + + + +++
Methotrexate
● Can be taken 7.5-15mg 1x weekly, may increase to 20-25mg once weekly depending on the patient’s
response. Alternatively, can be taken 2.5mg 3x weekly
Tocilizumab
● Only available in IV or SC
● SC given once every 2 weeks
Prednisone
● Taken 1dose/day before going to bed in oral form, but compared to the dosage of the other 2, this is more
frequent

4. Cost Criteria:
Cost Grading:
++++ least expensive of the choices
+++ 0r ++ - in between
+ most expensive

Table of Cost Grading:

Drug Choices Cost Cost/Week Cost Grading
Methotrexate 2.5mg / tablet: ₱10.04 ₱10.04 × 3 tablet = ₱30.12 ++++
Tocilizumab 80mg / 4mL vial: ₱8305.57 ₱8305.5 × 1 vial = ₱8305.5 +
Prednisone 10mg / tablet: ₱5.50 ₱5.50 × 7 tablets = ₱38.5 +++

5. Consolidated ESSC
Drug Choices Efficacy Safety Suitability Cost Grade
Methotrexate ++++ ++ ++++ ++++ 14
Tocilizumab +++ +++ ++ + 9
Prednisone +++ + +++ +++ 10

Drug History
Medication Indication Dose of Frequency Duration Route Drug-to-drug interaction
medication

Ibuprofen Pain 800mg 3 times daily Start: Oral Decreases the excretion of
reliever taking methotrexate, thus,
7months increasing risk of adverse
ago effects (nephrotoxicity,
bone marrow suppression,
GI toxicity, menstrual
dysfunction)

Take note if the patient has taken any of the following drugs. These increases the serum levels of MTX and may
precipitate severe adverse reactions:
● Ciprofloxacin, ciclosporin, penicillin, levetiracetam, probenecid, salicylates, sulfonamides, and PPI (e.g.
omeprazole, pantoprazole), phenylbutazone, phenytoin

Non-Pharmacologic
● Patient self-management education
● Transparency to attending physician
● Exercise
○ Low impact aerobic activities - brisk walking, cycling, swimming, light gardening, group exercises,
dancing
○ Muscle-strengthening exercises - lifting weights, using resistance bands, yoga
○ Flexibility exercises - yoga
 ○ Balance exercises - walking backwards, standing on one foot, tai chi
● Physical therapy
● Stress reduction
● Diet
○ One study found that mediterranean-style foods (olive oil, fish, greens, vegetables) had less joint pain
and morning stiffness
○ Limit alcohol intake
○ Other food that helps reduce inflammation: Berries, Avocado, Mushrooms, Tomatoes
○ Inflammatory foods: Junk foods, Refined Carbohydrates and sugars, Fried food, Trans fats
● Specific for MTX: avoid milk-rich foods, it will decrease the absorption of MTX

6. Write a complete and correct prescription order.

Commonly used treatment for RA: Methotrexate

- May be given orally, subcutaneous or intramuscularly
- Oral preparations (tablet form) may be given initially, 7.5-15 mg once weekly, may increase to 20-25 mg once
weekly, according to patient response. Alternatively, 2.5 mg 12 hourly for 3 doses once weekly.
- Subcutaneously, aso given 7.5 mg initially once weekly
- Should be taken on an empty stomach. Best taken on an empty stomach. May be taken w/ meals to reduce GI
discomfort. It should not be taken with milk-rich products
- Category X based on the index of drug safety in pregnancy.
- Studies in both animals and humans have demonstrated fetal abnormalities; there is evident fetal risk
based on human experience or both and the risk outweighs the possible benefit. Contraindicated in
women who are or may become pregnant.
- Pregnancy should be avoided 6 months after therapy of Methotrexate.
- Contraindicated with alcoholism, alcoholic liver disease or other chronic liver disease as well as psoriasis,
preexisting blood dyscrasias such as bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia and
immunodeficiency syndromes. Alcohol should be avoided while taking methotrexate as it can cause liver
damage.
- Folic Acid may be given to reduce chances of side effects as it helps protect the healthy cells in the body and
 reduces the possible side effects of methotrexate. It replenishes the folate lost by methotrexate. It is initially
taken as 1 tablet per week after a day of intake of methotrexate so as to not counteract the absorption of
methotrexate. If the patient is bothered with the side effects the doctor can prescribe 1 tablet 6 times a week
after a day of intake of methotrexate.

Other treatment for rheumatoid arthritis: Corticosteroids

● Corticosteroids may also be administered through injection to relieve the pain and inflammation of RA, this acts
specifically in the joints.
● Usually steroids are administered in lower doses for a longer duration until other meds start to control the
disease.
○ Adverse effects: osteoporosis, aseptic joint necrosis, adrenal insufficiency, gastrointestinal, hepatic, and
ophthalmologic effects, hyperlipidemia, growth suppression, and possible congenital malformations.
● However, studies have shown that there were more side effects for the administration of prednisone compared
to methotrexate. Thus methotrexate is the preferred medication as it seems to be the safer option with minimal
side effects

Methotrexate 1 tablet per week

Folic Acid 1 tablet per day after taking methotrexate

7. Monitor response to treatment.

● Laboratory monitoring
○ Erythrocyte sedimentation rate (ESR) - helps assess levels of inflammation in the body
○ C-reactive protein (CRP) - assess level of inflammation
○ Complete blood count (CBC) - used to rule out other possible causes of symptoms; rule out anemia
○ Liver function test - can be performed in cases of hepatotoxicity
○ Creatinine clearance - important to avoid nephrotoxicity
○ Test to eliminate presence of tuberculosis - to avoid reactivation of tuberculosis caused by the drug
○ Bone marrow toxicity test - as myelosuppression can occur in folate deficient patients
● Joint scans
○ X-rays, MRI scans, and ultrasound - can be used to check signs of wasting
○ Magnetic resonance imaging (MRI) and ultrasonography
■ Provide insight into the pathogenesis of inflammatory joint disease
■ Have the ability to identify the key pathologic features of the disease entity at presentation,
much earlier than they are seen on radiography
■ Both modalities are characterized by high sensitivity in depicting local inflammation in the form
of synovitis, tenosynovitis and bursitis, which is greater than in clinical examination and
conventional radiography and can help establish an early diagnosis in RA
○ X-rays
■ Traditionally used to detect RA and monitor for worsening of bone damage
■ May be preferred over MRI or ultrasound because of its lower cost
● Physical therapy assessment
○ Functional assessment (i.e., transfer status, analysis of gait, activities of daily living)
○ Range of joint motion (ROM) (for all joints)
○ Muscle strength test (manual or by isokinetic equipment)
○ Postural assessment
○ Evaluation of respiratory function
○ Presence of inflammation, instability, and contractures may affect the results of these evaluations and
tests. Scales such as Arthritis Impact Measurement Scale I and II, Health Assessment Questionnaire,
and Functional Independence Measure may be used for functional assessment.
● Complete list of previous medication - to avoid possible drug interactions
○ Ibuprofen
■ Adverse effects: gas, feeling bloated, heartburn, stomach pain, nausea, vomiting,
diarrhea/constipation
■ Contraindications: patient with known history of hypersensitivity/allergic reaction to the drug
itself, other NSAIDs, or aspirin
○ Methotrexate
 ■ Adverse effects: may cause mouth ulcers; nausea and vomiting; mild liver irritation
■ The concomitant use of methotrexate and omeprazole can increase the risk of toxicity of the
former because the coadministration of proton pump inhibitors can delay the excretion of
methotrexate and potentiate its adverse effects. Omeprazole serum concentrations decrease
rapidly after interruption of its use. Thus, patients receiving that association should be strictly
monitored to avoid possible damage resulting from the high concentration of methotrexate in
their bodies.
■ Blood work will be done every 4-12 weeks to check your liver function. This blood work will also
include a complete blood count (CBC) since methotrexate can also cause a decrease in blood
counts.
○ Corticosteroids
■ Adverse effects: increased risk of both bacterial and viral infections, cataracts, osteoporosis, GI
issues (e.g. bleeding, gastritis, gastric ulcer formation), cardiovascular diseases
● Improvement in condition will be seen around 3-6 weeks
● Full benefit of the drug (methotrexate) can be seen after 12 weeks