Pharmacology Lecture Slides on Rheumatoid Arthritis by Sanjaya Mani Dixit Assistant Professor of Pharmacology at Kathmandu Medical College

1. Rheumatoid Arthritis
Sanjaya Mani Dixit
Assistant Prof of Pharmacology

2. Contents
• Arthritis- Types
• RA – Introduction
• RA- Symptoms, Goals, Management
• Drugs for Treatment
– NSAIDs
– DMARDs
– TNF Inhibitors
– Corticosteroids
• Random facts
Rheumatoid Awareness Day
February 2nd

3. Rheumatoid Arthritis

4. Arthritis
• The word arthritis comes from the Greek
word “arthron” meaning "joint" and the
Latin “itis” meaning "inflammation".
• The plural of arthritis is arthritides.
• It is the main cause of disability among
people over 55 years of age in
industrialized countries.
• Arthritis is not a single disease - it is a
term that covers over 100 medical
conditions.
Pannus is an abnormal layer of fibrovascular tissue or granulation tissue, causing
loss of bone and cartilage

5. Rheumatoid Arthritis
• Unlike most forms of arthritis, rheumatoid arthritis
does not come from wear and tear on the joints but
is known as an inflammatory condition that stems
from the immune system.
• An external trigger (eg, cigarette smoking, infection,
or trauma) that triggers an autoimmune reaction,
leading to synovial hypertrophy and chronic joint
inflammation.
216 KD
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001467/
RA is an autoimmune disease in which there is joint
inflammation, synovial proliferation and destruction of articular
cartilage.
It is a poly-articular disease with the involvement of joints of hands
& feet.
Subsequent destruction of joints [deformities]

6. Rheumatoid Arthritis
Immune complexes composed of IgM activate complement
and release cytokines (mainly TNF-a and IL-1) which are
chemotactic for neutrophils.
These inflammatory cells secrete lysosomal
enzymes which damage cartilage and erode
bone, while PGs produced in the process cause
vasodilatation and pain.
RA is a chronic progressive, crippling
disorder with a waxing and waning course.
(3x)Females [20-50 years] > Males

7. Symptoms of RA
• RA usually affects joints on both sides of the body equally.
Wrists, fingers, knees, feet, and ankles are the most
commonly affected.
• The disease often begins slowly, usually with only minor
joint pain, stiffness, and fatigue.
Joint symptoms may include:
• Morning stiffness, which lasts more than 1 hour, is
common. Joints may feel warm, tender, and stiff when not
used for an hour.
• Over time, joints may lose their range of motion and may
become deformed.

8. Symptoms of RA
Other symptoms include:
• Chest pain when taking a breath (pleurisy)
• Dry eyes and mouth (Sjogren’s syndrome)
• Eye burning, itching, and discharge
• Numbness, tingling, or burning in the hands and
feet
• Nodules under the skin (usually a sign of more
severe disease)

9. Goals of therapy:
• The goals of drug therapy in RA are:
– Ameliorate pain, swelling and joint stiffness.
– Prevent articular cartilage damage and bony erosions
– Prevent deformity and preserve joint function.
RA usually requires lifelong treatment, including
medications, physical therapy, exercise, education, and
possibly surgery.
Early, aggressive treatment for RA can delay joint
destruction.

10. Management of RA
A. Early :
– Stop the inflammation to relieve pain
– Protect the unaffected joint cartilage
B. Late:
– Correction of deformity
– Improve the environment for the patient
C. Pharmacological measures
D. Non-pharmacological measures:
– Education and Emotional factors
– Physical therapies
– Rest (Complete body rest and articular rest )
– Heat and cold therapies
– Weight loss

11. Drugs in RA
A. NSAIDs (Non-steroidal anti-inflammatory drugs)
B. DMARDs/SAARDs (Disease modifying anti-rheumatic
drugs or slow acting anti-rheumatic drugs)
C. Biologic response modifiers
TNF-inhibitors: Etanercept, Infliximab
IL antagonists: Anakinra
D. Corticosteroids: Prednisolone, Triamcinolone

12. NSAIDs
• NSAID is often the first drug used in RA.
• Aspirin, Ibuprofen, Naproxen, Piroxicam, Diclofenac, Etodolac,
Celecoxib, Rofecoxib, etc.
• Helps alter the progression of disease.
M/A
• Inhibition of clyclooxygenase hence formation of PGs which cause
inflammation and pain is inhibited.
– COX-1- Stomach- PGE- mucosal cytoprotection
– COX-2 – Induced by cytokines, in inflammatory tissues
• COX-2 Inhibitors are less likely to cause GI effects.
• For RA all NSAIDs appear equivalent (CMDT).
• However, patients may respond differently to NSAIDs, an NSAID
that works for one may not work for another. Try another NSAID if it
does not work after 2-3 weeks.

14. DMARDs
• Immunosuppressants:
– Methotrexate,
– Azathioprine,
– Cyclosporine
• Sulfasalazine
• Antimalarials:
– Chloroquine
– Hydroxychloroquine
• Leflunomide
• Gold Sod. thiomalate, Auranofin
• d-Penicillamine

15. DMARDs
• They suppress the inflammatory process in rheumatoid
arthritis by inhibiting the production of cytokines
• Suppress ESR [Disease modifying agents]
• K/a slow acting anti-rheumatic drugs [weeks-months]
• Immune suppressants: retard radiological progression of
erosions
• Toxic [monitoring]
• Methotrexate, gold, d-penicllamine, azathioprine &
sulfasalazine: same but potent > hydroxychloroquine
• Methotrexate is better tolerated [1st choice]
• Sulfasalazine (2nd
choice)

16. Methotrexate
• Dihydrofolate reductase inhibitor
• Immunosuppressant and anti-inflammatory
P/A
Inhibition of cytokine production, chemotaxis and cell
mediated immune reaction.
Onset or relief of symptoms seen in 4-6 weeks (Gold,
penicillamine, antimalarials take 2-6 months), therefore
preferred as initial treatment option (DOC) including cases
of juvenile RA.
Initial therapy started with low oral dose 7.5-15mg weekly.
Max 20 mg

17. Methotrexate
S/E
Nodulosis, oral ulceration, GI upset, stomatitis
[SC or IM injection to decrease GI problems]
Prolonged use: Dose dependent liver toxicity—cirrhosis in some
[S/E reduced by folate 1mg daily or Leucovorin calcium 2.5-5mg 24 hrs after
methotrexate]
Cytopenia due to bone marrow suppression and infections.
C/I
Pregnancy, lactation, liver diseases, active infection, peptic ulcer.

18. Chloroquine & Hydroxychloroquine
• Hydroxychloroquine is the most often used drug against RA.
• Antimalarial drugs found to induce remission (absence of disease)
in upto 50% patients of RA, but take 3-6 months (long periods).
Advantage:
Relatively low toxicity (at dose 200-400mg/d), but efficacy is also
low; bony erosions are not prevented.

19. Chloroquine & Hydroxychloroquine
M/A: Unclear; Reduce monocyte IL-1, consequently inhibiting B
lymphocytes, decrease leukocyte chemotaxis, Lysosomal
stabilization, interfere with DNA and RNA synthesis and free
radical scavenging effect.
S/E:
Retinal damage and corneal opacity. (less in Hydroxy..)
[Opthalmologic examinations ever 6-12 months for long term
therapy]
Rashes, graying of hair, IBS,
Myopathy, neuropathy [improve when drug is withdrawn]

20. Auranofin
• Gold was considered to be the most effective agent for arresting the
rheumatoid process and preventing involvement of additional joints.
(P/O)
• Now it has been replaced by low dose Methotrexate.
M/A:
• It reduces chemotaxis, phagocytosis, macrophage and lysosomal
activity, monocyte differentiation and inhibits cell mediated immunity.
• It prevents joint destruction via its effect on synovial membrane and
collagen.
A/E:
• Diarrhoea, abdominal cramps, pruritis, taste disturbances, mild anemia,
alopecia.
• Parenteral Gold salt S/E: hypotension, dermatitis, stomatitis, kidney and liver
damage, bone marrow depression.

21. d-Penicillamine
• Copper chelating agent
• It is prescribed primarily for patients with persistent aggressive
disease who have failed other available DMARDS.
• Has gold-like action in RA, but less efficacious; bony erosions do
not heal.
• Not much preferred now, owing to low risk: benefit ratio.
• Careful monitoring of kidney function is required with this drug.
• A/E:
– Loss of taste,
– Systemic lupus &
– Myasthenia gravis
– Effects on renal function

22. TNF-a inhibitors
• Fulfils the aim of targeted therapy for RA;
expensive.
• Treatment for patients not responding to
Methotrexate therapy (60%).
• TNF-a plays a key role in the inflammatory
reaction of RA by activating membrane bound
receptors (TNFR1 and TNFR2) on the surface of
T-cells, and macrophages.
• TNF inhibiting recombinant proteins or
monoclonal antibodies neutralize it and its action.

23. TNF-a inhibitors
• They mainly suppress macrophage and T-cell function,
inflammatory changes in the joint regress and slows
new erosions.
• Quicker response than DMARDs has been seen, and
are effective as monotherapy, however, is given in
combination. Concomitant methotrexate & infliximab,
enhances the clinical response and prevents the
development of neutralizing antibodies to the drug.
S/E: susceptibility to opportunist infections like TB,
pneumonia.
[TNF has physiologic role in combating infection]

24. TNF-a inhibitors
Ethenercept
• It is a recombinant fusion protein comprising 2 TNF receptors linked to
immunoglobulin, acts as a decoy receptor decreasing the cellular actions of TNF-
alpha.
• It is given as SC inj 25mg weekly.
• Pain, redness, itching and swelling
• Also effective in t/o JRA (Juvenile RA).
Infliximab
• Infliximab is a chimeral monoclonal antibody that binds and neutralizes TNF-a. It is
given IV every 4-8 weeks at 3-5 mg/kg body wt.
• An acute reaction comprising of fever, chills, urticaria, bronchospasm, and rarely
anaphylaxis.
• Susceptibility to respiratory infections is increased and worsening of CHF has
been noted.
• Clinical improvement is associated with decrease in CRP (C Reactive protein).

25. Corticosteroids
• Potent immunosuppressant and anti-inflammatory
• Prompt symptomatic relief, but do not arrest the rheumatoid
process, joint destruction may be slowed and bony erosions delayed.
• Started at any stage in RA along with first or second line drugs, as
adjuvant to NSAIDs + DMARDs.
• May be used in short term basis:
– to treat the disabling episodes ,
– Temporary control of severe exacerbations
– as adjunct to physiotherapy,
– to manage serious extra-articular manifestations (Eg, pericarditis, perforating
eye lesions)
• Long term use has serious disadvantages, therefore low doses (5-10
mg prednisolone) used to supplement NSAIDs or high doses are used
for short periods in cases of systemic manifestations like vasculitis.

26. Corticosteroids
• In cases with single or few joint involvement with
severe symptoms, intraarticular injection of a soluble
glucocorticoid affords relief for several weeks
(Triamcinolone 10-40 mg depending upon the joint size);
joint damage may be slowed.
• S/E-
– Stomach irritation, such as indigestion
– Tachycardia, nausea, insomnia, metallic taste
– Weight gain, thinning skin, muscle weakness, weakening of
bones (osteoporosis), high blood pressure
– Oral corticosteroids increase vulnerability to infection by
viruses chicken pox, measles.

27. Sulphasalazine
• Second line agent for RA.
• Dose 0.5g BD increased weekly to max 3gm/day.
• It may take 6 weeks to 3 months to see the effects of sulfasalazine.
• It is also given in conjunction with methotrexate and hydroxychloroquine as part
of a regimen of “triple therapy” which has been shown to provide benefits to
patients who have had inadequate responses to methotrexate alone.
• M/A in RA in unknown, may be d/t folate depletion.
• It is a Sulphur combined with a salicylate.
• Sulphasalazine (Sulfapyridine moiety+ 5-amino salicylic acid moiety)
RA treatment Mesalamine drug-Ulcerative colitis
S/E
– Neutropenia and thrombocytopenia
– Hemolysis in G6PD patients (blacks).
• Complete Blood Count monitoring required ever 2-4 weeks for 3 months then
every 3 months.

28. Leflunomide
• Prodrug; inhibits enzyme dihydroorotate
dehydrogenase, an enzyme required by activated
lymphocytes for synthesis of pyrimidines needed
for RNA synthesis- leading to cell cycle arrest in
lymphocytes.
• Other cells use other biochemical pathways for
pyrimidine synthesis and hence not much
affected.
• S/E diarrhoea, rash, hepatotoxicity, alopecia, wt
loss
• Carcinogenic and teratogenic, CI in willing to be
parents.

29. Random Facts
Pyramid treatment style
• Traditional treatment of RA involved the use of drugs in a pyramidal fashion:
– 1st
minimally toxic but less effective drugs,
– 2nd
more potent but more toxic drugs for more severe and advanced forms of disease.
• Thus, DMARDs and corticosteroids were given at last, now evidence shows that
early treatment with DMARDs improves the quality of life and long term
outcome in RA patients.
Current trend
• Combination of NSAID+ DMARD (Methotretxate, Hydoxychloroquine,
Sulfasalazine)-quick relief and possible arrest of disease progression. Delays
bone damage too.
• In severe cases glucocorticosteroids added at onset, large initial doses tapered
to a maintenance dose.
Satoskar

30. Rheumatoid factor
Rheumatoid factor is an immunoglobulin (antibody) which can be tested
for its presence in the blood. Rheumatoid factor though is not normally
found in the general population (only found in about 1-2% of healthy
people). The incidence of rheumatoid factor increases with age and about
20% of people over 65 years old have an elevated rheumatoid factor.
The blood test is commonly ordered to diagnose rheumatoid arthritis.
Rheumatoid factor is present in 80% of adults who have rheumatoid
arthritis but there is a much lower prevalence in juvenile rheumatoid
arthritis. The incidence of rheumatoid factor increases with duration of
disease in rheumatoid arthritis: at 3 months the incidence is 33%, while at
one year it is 75%. Up to 20% of rheumatoid arthritis patients remain
negative for rheumatoid factor (also known as "seronegative rheumatoid
arthritis") throughout the course of their disease. Patients with Sjögren
syndrome will be persistently negative for RF and/or may have very low
levels of RF.

31. References
• Essentials of Pharmacology --KD Tripathi
• Pharmacology and Pharmacotherapeutics- Satoskar
• Basis of Clinical Pharmacology-Katzung
• CMDT-Current medical diagnosis and treatment
• Pharmacology Examination and board review-Katzung and
Trevor
• http://www.hopkins-arthritis.org/arthritis-info/rheumatoid-ar
thritis/rheum_treat.html

32. That’s All
ENJOY
32

33. www.medipuzzle.com
Trusted by
10K + Students