This document provides information on antirheumatic drugs used to treat rheumatoid arthritis (RA). It describes the pathophysiology of RA involving inflammatory cytokines like TNF, IL-6, IL-1. NSAIDs provide initial symptomatic relief but DMARDs like methotrexate, hydroxychloroquine, leflunomide, and sulfasalazine suppress disease progression. Biological DMARDs targeting TNF or non-TNF pathways like abatacept are used when traditional DMARDs are ineffective. The goals of treatment are to reduce symptoms, prevent joint damage, and maintain function. Adverse effects of various drugs are also outlined.

1. Antirheumatic drugs
Dr. M. Ahsan (MBBS, MD)

2. Learning Outcomes…
• Describe the pathophysiology of rheumatoid arthritis
• Describe the goal of therapy in rheumatoid arthritis
• Classify the drugs used in rheumatoid arthritis
• Describe the pharmacodynamics and pharmacokinetics of Disease
Modifying Antirheumatic Drugs (DMARDs)
• Describe the role of Biological Disease Modifying Antirheumatic drugs

3. Rheumatoid arthritis
• Rheumatoid arthritis (RA) is an autoimmune disease in which there is:
 joint inflammation
synovial proliferation
destruction of articular cartilage
• It is a chronic progressive, crippling disorder with a waxing and
waning course

4. Features of RA
• Tender, warm, swollen joints
• Symmetrical pattern of affected joints
• Joint inflammation often affecting the wrist and finger joints closest to the
hand
• Joint inflammation sometimes affecting other joints, including the neck,
shoulders, elbows, hips, knees, ankles, and feet
• Fatigue, occasional fevers, a general sense of not feeling well
• Pain and stiffness lasting for more than 30 minutes in the morning or after
a long rest
• Symptoms that last for many years
• Variability of symptoms among people with the disease

5. Pathophysiology of RA
• Synovitis in RA is triggered when chemoattractants
produced in the joint recruit circulating inflammatory
cells.
• These inflammatory cells secrete lysosomal enzymes
which damage cartilage and erode bone, while PGs
produced in the process cause vasodilatation and pain.
• Overproduction of tumour necrosis factors (TNF) is a key
inflammatory element in RA
• Interleukin-6 and interleukin-1 are also involved
Key cytokines
involved in
RA:
• TNF
• IL-6
• IL-1

6. Pathophysiology of RA

7. Causes
• Genetic (inherited) factors.
• Environmental factors: viral or bacterial infections.
• Other factors: hormonal changes, pregnancy, breastfeeding,
contraceptives.

8. Diagnosis
• Medical history.
• Physical examination.
Other lab tests:
a blood test for anemia, which is
common in rheumatoid arthritis.
ESR (erythrocyte sedimentation
rate) which measures
inflammation in the body.
C-reactive protein is useful in
making a diagnosis
Laboratory tests:
Rheumatoid factor (RF)
Anti-CCP antibodies

9. Current treatment approaches
• Lifestyle changes
• Medications
• Surgery
• Routine monitoring and ongoing care.

10. Goal 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
NSAIDs are the first line drugs and afford symptomatic relief in pain,
swelling, morning stiffness, immobility, but do not arrest the disease
process

11. NSAIDs
• Non-steroidal anti-inflammatory drugs
• NSAIDs are a large class of medications useful against pain and
inflammation.
• Most NSAIDs act as nonselective inhibitors of the enzyme
cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1)
and cyclooxygenase-2 (COX-2) isoenzymes. COX catalyzes the
formation of prostaglandins and thromboxane from arachidonic
acid.

12. NSAIDs
Non-selective COX inhibitors
Preferential COX-2 inhibitors
Selective COX-2 inhibitors
Anlagesic-antipyretics with poor anti-inflammatory action

13. NSAIDs
Non-selective COX inhibitor:
• Salicylates - Aspirin
• Proprionic acid derivative –
Ibuprofen, naproxen, ketoprofen,
flurbiprofen
• Fenamate – mephenamic acid
• Enolic acid derivative – piroxicam,
tenoxicam
• Acetic acid derivative – ketorolac,
indomethacin, nabumetone
• Pyrazolone derivative –
phenylbutazone, oxyphenbutazone
Preferrential COX-2 inhibitors:
• Nimesulide, Diclofenac,
Aceclofenac, Meloxicam, Etodolac
Selective COX-2 inhibiors (Coxibs):
• Celecoxib, Etoricoxib, Parecoxib
Analgesic-antipyretic with poor
antiinflammatory action:
• Paracetamol, Nefopam

14. NSAIDs
• NSAIDs can cause stomach irritation or, less often, can affect kidney
function.
• Many other drugs cannot be taken when a patient is being treated
with NSAIDs because they alter the way the body uses or eliminates
these other drugs.
• NSAIDs sometimes are associated with serious gastrointestinal
problems, including ulcers, bleeding, and perforation of the stomach
or intestine.
• People over age 65 and those with any history of ulcers or
gastrointestinal bleeding should use NSAIDs with caution.

15. Antirheumatic drugs
Suppress the rheumatoid process
Bring about a remission
Retard disease progression
But do not have nonspecific antiinflammatory or analgesic action.
• They are used in rheumatoid arthritis (RA) in addition to NSAIDs and
are also referred to as disease modifying antirheumatic drugs
(DMARDs)
Take a few weeks or
months to have an
effect

16. Classification of drugs
Traditional Disease modifying antirheumatic drugs (DMARDs)
• Immunosuppressants: Methotrexate, Azathioprine, Cyclosporine
• Hydroxychloroquine
• Sulfasalazine
• Leflunomide
Biological Disease Modifying Antirheumatic Drugs
• TNF α inhibitors: Adalimumab, Certolizumab, Etanercept, Golimumab,
Infliximab
• Non-TNF inhibitors: Abatacept, Rituximab, Tocilizumab, Anakinra
Adjuvant drugs: Glucocorticoids

17. Methotrexate (Mtx)
• Mtx is a dihydrofolate reductase inhibitor
• It has prominent immunosuppressant and antiinflammatory property
• Beneficial effects in RA is due to inhibition of cytokine production,
chemotaxis and cell-mediated immune reaction
• It is administered once weekly
• In RA, Mtx dose is much lower (7.5 – 15 mg) than those needed in
cancer chemotherapy
• Response occurs within 3 to 6 weeks of therapy
Mtx - DMARD of first
choice

18. Methotrexate
• Oral bioavailability of Mtx is variable and may be affected by food.
• Excretion of Mtx is decreased in renal disease: not recommended for
patients of renal disease
• Probenecid and aspirin increase Mtx levels and toxicity.
• Trimethoprim (dihydrofolate reductase inhibitor) can add to inhibition
of dihydrofolate reductase

19. Adverse effects of Methotrexate
• Common adverse effects:
mucosal ulceration and nausea
• Bone marrow suppression
• Cytopenias, cirrhosis of liver and
acute pneumonia like syndrome
may occur with chronic
administration
• Methotrexate is contraindicated
in pregnancy
Recommendations:
• Periodic liver function testing
• Complete blood counts
• Monitoring signs of infection
Supplementation with folic acid or
leucovorin may improve
tolerability

20. Hydroxychloroquine
• Antimalarial drug which induces
remission in upto 50% patients
of RA
• Used for early, mild RA
• May be combined with MTx
• Hydroxychloroquine has less
adverse effects on the liver and
immune system than other
DMARDs
• It may cause ocular toxicity,
irreversible retinal damage and
corneal deposits
• Advantage is relatively low toxicity, but
efficacy is also low
• Onset of effect takes 6 weeks to 6
months
Mechanism of actions:
 Reduce monocyte IL–I, consequently
inhibiting B lymphocytes.
 Antigen processing may be interfered
with.
 Lysosomal stabilization and free radical
scavenging are the other proposed
mechanisms.

21. Leflunomide
• It is an immunomodulator
• Inhibits proliferation of stimulated lymphocytes in patients with
active RA.
• Arthritic symptoms are suppressed and radiological progression of
disease is retarded
• Onset of benefit is as fast (4 weeks).

22. Leflunomide
• Rapidly converted in the body to
an active metabolite which is a
reversible inhibitor of
dihydroorotate dehydrogenase
(DHODH)
• DHODH is an enzyme necessary
for pyrimidine synthesis
• Active metabolite has a long t½
(2–3 weeks)

23. Leflunomide
Adverse effects:
Diarrhoea, headache, nausea
(common)
Weight loss, allergic reactions,
flu-like syndrome, alopecia,
hypokalemia
• Not recommended in liver
disease as it is hepatotoxic
• Contraindicated in pregnancy
• Can be used alone or in
combination with Mtx
Monitor:
 Signs of infections
 CBC
 Electrolytes
 Liver enzymes

24. Sulfasalazine
• Compound of sulfapyridine and 5-amino salicylic acid (5-ASA);
• Sulfapyridine is the active moiety in RA.
• It is split off in the colon by bacterial action and absorbed systemically
(contrast ulcerative colitis, in which 5-ASA acting locally in the colon is
the active component)
• Generation of superoxide radicals and cytokine elaboration by
inflammatory cells may be suppressed.
• It is used as a second line drug for milder cases or is combined with
Mtx.
Side effects: GI adverse effects (nausea, vomiting, anorexia) and leukopenia
Onset of activity –
1 to 3 months

25. Biological DMARDs
• Biologic DMARDs are used when there is inadequate response to
traditional DMARDs
• Clinical response is seen within 2 weeks of therapy
• TNF-α inhibitors or non-TNF inhibitors can be used
• Patients on biological DMARDs are at an increased risk of infections
like tuberculosis, fungal infections and sepsis
• Live vaccines cannot be administered in patients taking biologic
DMARDs

26. Biological DMARDs
TNF-α inhibitors
• Adalimumab
• Certolizumab
• Etanercept
• Golimumab
• Infliximab
Non- TNF biological
agents
• Abatacept
• Rituximab
• Tocilizumab
• Anakinra

27. Biological DMARDs
Adalimumab
• Recombinant monoclonal antibody
• Binds to TNF and interferes with its
activity
• Given subcutaneously weekly or on
alternate weeks
• S/E: headache, nausea,
agranulocytosis, rash, injection site
reaction, increased risk of infection
Certolizumab pegol
• Humanized monoclonal antibody
• Binds to TNF
• Combined with polyethylene glycol
• Given subcutaneously every 2
weeks
• S/E: Similar to other TNF inhibitors

28. Biological DMARDs
Etanercept
• Fusion protein
• Binds to TNF and blocks its
interaction with cell surface
receptors
• Given subcutaneously once a
week
• Combination with Mtx improves
function and achieves remission
in RA
Infliximab
• Chimeric monoclonal antibody
• Binds to TNF and inhibits binding
with its receptors
• Given as iv infusion every 8
weeks
• Infusion related reactions can
occur
• Not indicated for monotherapy
due to development of anti-
infliximab antibodies

29. Biological DMARDs
Abatacept
• Recombinant fusion protein and
costimulation modulator
• Competes with CD28 for binding on
CD80/CD86 protein
• Prevents full T-cell activation and
thus reduces inflammation
• Given as iv infusion every 4 weeks
• S/E: infusion relation reaction,
hadache, upper respiratory
infections, nausea
Rituximab
• Chimeric monoclonal antibody
• Binds with CD20 on surface of
normal and malignant B cells
• Results in B cell depletion
• Given as iv infusion every 16-24
weeks
• Methylprednisolone is given 30
mins prior to infusion to decrease
infusion reactions

30. Biological DMARDs
Tocilizumab and Sarilumab:
• They are monoclonal antibodies that bindto IL-6 receptors
• They inhibit activity of the pro-inflammatory cytokine IL-6
• Given as subcutaneous injection every 2 weeks

31. Glucocorticoids
• They are potent anti-inflammatory drugs used in RA to:
Provide symptomatic relief
Bridge the time until other DMARDs become effective
• Glucocorticoids should always be used at the lowest dose and for the
shortest duration possible

32. Glucocorticoids
• Used in all stages of RA, along with first line or second line drugs
…….Can be given orally or intra-articularly
• Symptomatic relief is marked but they don’t arrest the rheumatoid
process
• Long term use of corticosteroids carries serious disadvantages

33. Therapy with DMARDs
Monotherapy may be initiated with any of the traditional DMARDs
Methotrexate is generally preferred
For patients with inadequate response to monotherapy,
Combination of traditional DMARDs, or use of a TNF inhibitor or non-TNF
biological agent may be needed
• NSAIDs and glucocorticoids can also be used
Early intervention with
DMARDs improves outcome

35. Azathioprine
• Immunosupressive agents….used mostly in kidney transplant rejection
prophylaxis
• Also useful in autoimmune conditions such as RA
• Purine synthase inhibitor
• Converted to 6-MP …. Chemical analog of purine: adenine, guanine,
hypoxanthine
• MOA: suppresses CMI
Affects differentiation and function of T-cells and natural killer cells

36. Cyclosporine
• Inhibits interleukin-1 and interleukin-2 receptor production and
secondarily inhibits macrophage–T-cell interaction and T-cell
responsiveness
• First used in organ transplantation to prevent rejection.
• It is used in patients who have not responded to other drugs.
• Grapefruit juice increases cyclosporine bioavailability by 62%.
• It is metabolized by CYP3A and consequently is subject to a large number
of drug interactions
• Side effects: Bleeding, tender, or enlarged gums; high blood pressure;
increase in hair growth; kidney problems; trembling and shaking of hands.

37. Anakinra
• A recombinant nonglycosylated form of the human IL-1 receptor
antagonist (IL-1ra).
• occupies the IL-1 receptor without triggering it and prevents receptor
binding of IL-1.
• A significant response was observed in approximately 40% of
patients with RA.
• The risk of infection, primarily bacterial, appears to be increased.
Serious infections occurred in 2.1percent patients receiving anakinra

38. Gold salts (Gold sodium thiomalate)
• Proposed mechanism: inhibits macrophage activation.
• Side effects: Redness or soreness of tongue; swelling or bleeding
gums; skin rash or itching; ulcers or sores on lips, mouth, or throat;
irritation on tongue. Joint pain may occur for 1 or 2 days after
injection.
• Gold injections have been used in the treatment of RA for close to
century-initially intramuscular and, more recently, orally.
• With advent of newer agents, gold is rarely used in most part of
world.

39. Thank you

40. References
• Lippincott Illustrated Reviews: Pharmacology(6th ed.). Philadelphia,
PA: Wolters Kluwer.
• Clinical Medicine: A Textbook for Medical Students & Kumar PJ
and Clark ML (8th ed.); Elsevier Saunders
• Disease-Modifying Anti-Rheumatic Drugs (DMARDs) used for
Rheumatoid Arthritis- A review. Indian Journal of Basic and Applied
Medical Research; June 2015: Vol.-4, Issue- 3, P. 272-288
• Managing the drug treatment of rheumatoid arthritis. Australian
prescriber. VOLUME 40 : NUMBER 2 page 51-58 : APRIL 2017