Department of clinical Pharmacology

Prof: Mervat Eid

OBJECTIVES
 List the classes of drugs that are used in the treatment
of RA
 Describe the mechanism of action, pharmacokinetics
and adverse effects of the above drugs
 Explain the basis of disease modifying drugs
Who gets RA?
 ANYONE CAN GET RA
 From babies to the very old
 Common Age to Start: 20’s to 50’s
 Sex: Females more common than males 3:1
How does RA start?
 RA usually starts off slowly (insidious) over weeks to
months and progresses (70%)
 It can come on overnight (acute) but this is rare (10%)
 It can come on over a few weeks (subacute – 20%)
Rheumatoid arthritis
 Chronic synovial inflammation

 Autoimmune

 Cytokine networks are responsible for inflammation &

joint destruction
 Tumor Necrosis Factor-α (TNF-α)
 Interleukins - 1,6,17
How does RA start?
 Initially, most patients notice stiffness of the joints
which seems more pronounced in the morning
 Some fatigue
 Some pain
What Joints are affected?
 RA usually begins as an oligoarticular process (<5
joints) and progresses to polyarticular involvmement
 Has a predilection for the small joints of the hands and
feet!
How are the Joints Affected
 Joints are usually
 Swollen
 Warm

NOT RED (might be a bit purple)

Disability in Early RA
 Inflammation
 Swollen
 Stiff
 Sore
 Warm
 Fatigue
 Potentially Reversible
Small Joints of the Hand
What Joints are affected?
Disability in RA
 Most of the disability in RA is a result of the INITIAL
burden of disease
 People get disabled because of:
 Inadequate control
 Lack of response
 Compliance
 GOAL: control the disease early on!
Rheumatoid Arthritis is …
1. Usually insidious in onset
2. Adds joints over time
3. Has a predilection for the small joints of the
hands and feet
4. Joints become warm and swollen but not red
5. Morning stiffness is greater than 1 hour
6. Patients are often tired and don’t sleep properly
7. Can result in significant disability very quickly
Doesn’t just affect the joints

EXTRA-ARTICULAR
MANIFESTATIONS
Xerophthalmia (Dry Eyes)
Xerostomia (Dry Mouth)
Raynaud’s Phenomenon
Carpal Tunnel Syndrome
Pleural Effusion
Rheumatoid Nodules
Rheumatoid Vasculitis
 Maintain
Induce Remission
Remission
Drugs for RA
 Disease-modifying anti-rheumatic drugs (DMARDs)
 Synthetic
 Biologic

 Nonsteroidal anti-inflammatory drugs (NSAIDs)

 Glucocorticoids
NSAIDs
 Cyclo-oxygenase inhibitors

 Do not slow the progression of the disease

 Provide partial relief of pain and stiffness

NSAIDs
 Non-selective COX inhibitors
 Ibuprofen
 Diclofenac sodium

 COX–2 inhibitors
 celecoxib
COX-2 Inhibitors
 COX-2 inhibitors appear to be as effective NSAIDs

 Associated with less GI toxicity

 However increased risk of CV events

Read

Side effects of
 non selective NSAID
 COX – II inhibitors
Drugs for RA
 Nonsteroidal anti-inflammatory drugs (NSAIDs)

 Disease-modifying anti-rheumatic drugs (DMARDs)

 Synthetic
 Biologic

 Glucocorticoids
Glucocorticoids
 Potent anti-inflammatory drugs
 Serious adverse effects with long-term use
 To control the diaseas
 Indications
 As a bridge to effective DMARD therapy

 Systemic complications (e.g. vasculitis)

Route of steroid

Oral
Intra- articular
IM - depot
90% of the joints involved in RA are affected within
the first year

SO TREAT IT EARLY
Disability in Late RA (Too Late)
• Damage
– Bones
– Cartilage
– Ligaments and
other structures
• Fatigue
• Not Reversible
 Work

Cooking

Dressing
Cleaning Pleasure
Bathing
Grooming

Shopping
DMARDs
Disease Modifying Anti-Rheumatic Drugs
 Reduce swelling & inflammation
 Decrease pain
 Improve function
 (6 w to 6 m for full effect) Contraception??? Live
vaccine ??
 Have been shown to reduce radiographic progression
(erosions)
DMARDs in mild or early RA
1-Hydroxy chloroquine
 Block toll-like r
 ↑↑PH of lysosomes-----↓cellular processing
 Affect immune function (phagocytosis, chemotaxis
and oxidative activity)

Side effects

 Irreversible Retinal toxicity, corneal deposits

 Ophthalmologic evaluation every 6 months

2-Sulphasalazine (pro drug)
 Sulphapyridine + 5-aminosalicylic acid

 GI, hematologic,oligospermia and megaloplastic

anemia (side effects)
3- Minocycline
 It acts by: 1-inhibiting apoptosis
 2-Downregulating pro-inflammatory cytokines
 3-Inhibits collagenases and gelatinases.
 Side effects: autoimmune hepatitis
 GI,hypersensitivity reactions, hyperpigmentation and
intracranial hypertension
4- Oral gold salts
 It interfere with the uptake and binding of molecules
to MHC class II protein.
 2-inhibit IL-1B and TNF-α
 Diarrhea, rash, stomatitis,myelosuppression and
proteinuria.
 N.B: The major histocompatibility complex (MHC) is a
set of cell surface proteins essential for the acquired
immune system to recognize foreign molecules .
DMARDs in moderate to severe
RA
Methotrexate
Leflunomide
TNF-α inhibitors (infliximab)
Recombinant IL-1r antagonism ( Anakinra)
Abatacept
Rituximab
1-Methotrexate (MTX)
 Dihydrofolate reductase inhibitor.
 Stimulate release of adenosine
 ↓ thymidine & purine nucleotide synthesis
 Inhibit cytokine production
 “Gold standard” for DMARD therapy
 Elimination mainly renal
MTX adverse effects
 Hepatotoxicity
 Bone marrow suppression
 Dyspepsia, oral ulcers
 Pneumonitis
 Teratogenicity

 Folic acid reduces GI & BM effects

2-Leflunomide
 Competitive inhibitor of dihydrorotate dehydrogenase
(rate-limiting enzyme in de novo synthesis of
pyrimidines)

 Reduce lymphocyte proliferation

Leflunomide cont
 Oral
 Elimination hepatic

 Liver toxicity
 Avoid pregnancy for 2 years
Common DMARD
Combinations
• Triple Therapy
– Methotrexate, Sulfasalazine, Hydroxychloroquine
• Double Therapy
– Methotrexate & Leflunomide
– Methotrexate & Sulfasalazine
– Methotrexate & Hydroxychloroquine
– Methotrexate & Gold
3-Tumour Necrosis Factor (TNF-α)
biologic agent
 TNF is a potent inflammatory cytokine
 TNF is produced mainly by macrophages and
monocytes

 TNF is a major contributor to the inflammatory

and destructive changes that occur in RA

 Blockade of TNF results in a reduction in a

number of other pro-inflammatory cytokines (IL-1,
IL-6, & IL-8)
 TNF Receptor
How Does
TNF Exert Its
Effect?
Any Cell

Trans-Membrane
Bound TNF

Macrophage

Soluble TNF
Strategies for Monoclonal Antibody (Infliximab & Adalimumab)
Reducing
Effects of TNF

Trans-Membrane
Bound TNF

Macrophage

Soluble TNF
Side Effects
 Skin reaction
 Hepatotoxicity
 Infection: Common (Bacterial)
Opportunistic (Tb)
 Demyelinating Disorders
 Malignancy
 Worsening CHF
 4-Recombinant IL-1r antagonism ( Anakinra) (BA)
 Sc daily---skin irritaion,infection and leucopenia.
 5-Abatacept(BA)
 Fusion protein CD80/CD86 receptors on antigen
presenting cells.
 It inhibits interaction between antigen presenting cells
and T cells---preventing it from activation
 Reduction in cytokines and T-cell proliferation
 Dizziness, cough, back pain, hypertension and rash
 6-Rituximab (BA)
 Monoclonal antibody directed against CD20, protein
found on the surface of B cells----its depletion.
DMARDs less commonly used
for moderate to severeRA:
 1- Cyclosporine: Cacineurin inhibitor---block
signaling pathway of T cell r
 2-Parenteral gold
 3-D-penicillamine: Chelating agent
 4-Azathioprine
end