This document summarizes the pharmacotherapy of rheumatoid arthritis (RA). It discusses the pathogenesis of RA and the goals of treatment. It describes the classes of drugs used including nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs. The standard treatment protocol is to use methotrexate as first-line therapy and consider tumor necrosis factor (TNF) inhibitors or other biologics for patients with inadequate response. Combination therapy with methotrexate and a biologic is superior to methotrexate alone. Special considerations are discussed for pregnancy, elderly patients, and non-pharmacologic therapy.

1. PHARMACOTHERAPY OF
RHEUMATOID ARTHRITIS(RA)
Dr ShindeVirajAshok
JuniorResident-2
Dept.ofPharmacology
GMC Nagpur

2. Overview
Definition
Pathogenesis
Classification of drugs
Standard treatment protocol
Special population

3. Definition

4. Pathogenesis
 Immune complexes composed of IgM activate
complement and release cytokines –
chemotactic to neutrophils
 Inflammatory cells secrete lysosomal enzymes
which damage cartilage and erode bone while
prostaglandins cause vasodilatation and pain
 Chronic progressive , crippling disorder with a
waxing and waning course

5. Pathogenesis of rheumatoid arthritis. The figure summarises some of the cytokines and
cellular interactions believed to be important in RA. The molecular targets for biologic
agents currently used in the treatment of RA are shown. It is thought that TNF plays a
particularly important role by orchestrating production of other cytokines. (IL =
interleukins; MMP = matrix metalloproteinases; PGE = prostaglandin E; TCR = T-cell
receptor; TNF = tumour necrosis factor; VEGF = vascular endothelial growth factor)

6. Role of Non Steroidal Anti Inflammatory
Drugs(NSAIDs)
 First line drugs afford symptomatic relief in pain ,
swelling , morning stiffness , immobility
 Relatively rapid improvement compared with
Disease modifying antirheumatic drugs
(DMARDs), which may take weeks to months
before benefit is seen
 No impact on disease progression

7. Pharmacotherapy
 Goals of Treatment :
 To induce complete remission or low disease
activity
 To control
 Disease activity & joint pain
 Maintain ability to function in daily activities
 Slow destructive joint changes &
 Delay disability

8. Classification
 Disease modifying antirheumatic drugs
(DMARDs)
 Non biological drugs
 Immunosuppressants – Methotrexate , Azathioprine ,
Cyclosporine
 Sulfasalazine
 Chloroquine or Hydroxychloroquine
 Leflunomide
 Biological agents
 TNF α inhibitors : Etanercept, Infliximab , Adalimumab
 IL- 1 antagonist : Anakinra
 Adjuvant drugs
 Corticosteroids : Prednisolone and others

9. Nonbiologic DMARD
Methotrexate
 Dihydrofolate reductase inhibitor
 Inhibits
 Cytokine production
 Purine biosynthesis
 Stimulate adenosine release
DMARD of first
choice

10. Methotrexate
 Oral low dose (7.5 – 15mg) weekly – improved
acceptability of this drug
 Onset - early as 4 to 6 weeks
 Contraindicated
 Pregnant and nursing women
 Chronic liver disease
 Creatinine clearance of less than 40 ml/min

11. Methotrexate
 Oral bioavailability – variable & affected by
food
 Probenecid & aspirin increases its levels and
toxicity
 Adverse events – oral ulceration and
gastrointestinal upset

12. Azathioprine
 6-Thioguanine – major metabolite - Suppresses
inosinic acid synthesis, B-cell and T-cell function,
immunoglobulin production and interleukin-2 secretion
 Adverse effects - Bone marrow suppression, GI
disturbances, & some increase in infection risk
 Dose – 50 - 150mg/day
Primarily used - Steroid sparing
effect

13. Leflunomide
 Immunomodulator – inhibits proliferation of stimulated
lymphocytes
 Rapidly converted to active metabolite – inhibits
dihydroorotate dehydrogenase & pyrimidine synthesis
in actively dividing cells
 Arthritic symptoms are suppressed and radiological
disease progression is retarded
 Efficacy rated comparable to methotrexate

14. Leflunomide
 Onset of action – 4 weeks
 Active metabolite has long t1/2
 Loading dose 100mg daily for 3 days followed by
20mg OD
 Contraindicated
 Preexisting liver disease
 Pregnancy

15. Chloroquine & Hydroxychloroquine
 Induce remission in 50% patients of rheumatoid arthritis
 Used in mild RA or
 Especially when one or few joints are involved or
 Adjuvant in combination DMARD therapy

16. Chloroquine & Hydroxychloroquine
 Onset delayed for up to 6weeks
 Therapeutic failure – 6 months of therapy with no response
 Hydroxychloroquine preferred over chloroquine
 Periodic ophthalmologic examination - early detection of
reversible retinal toxicity
 Dose – Chloroquine 150mg/day
Hydroxychloroquine 400mg /day for 4 -6 weeks fb 200mg for
maintenance

18. Sulfasalazine
 Antirheumatic effects - Seen within 2 months
 Efficacy in RA is modest
 Side effetcs are unpleasant – neutropenia thrombocytopenia
in 10 % patients and hepatitis
 Used as second line drug for milder cases or is combined
with methotrexate
 Dose – 1 – 3 gm /day

19. Tofacitinib
 Nonbiologic JAK inhibitor
 Moderate to severe RA - Failed or have
intolerance to MTX
 Labeling includes black-box warnings
 Serious infections
 Lymphomas
 Live vaccinations – should not be given

20.  Gold – auranofin
 d –Penicillamine
 No longer used drugs Due to
 Higher toxicity
 Replacement by better drugs

21. Biologic agents

22. Tumour Necrosis Factor (TNF)
 Potent inflammatory cytokine
 Produced mainly by macrophages and
monocytes
 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)

23. Macrophage
Any Cell
Trans-Membrane
Bound TNF
TNF Receptor
Soluble TNF
How Does
TNF Exert Its
Effect?

25. Trans-Membrane
Bound TNF
Soluble TNF
Strategies for
Reducing
Effects of TNF
Macrophage
Monoclonal Antibody

26. Biologic DMARDs
 Used when non biologic DMARDs fail
 Considerably more expensive
 TNF-α inhibitors
 First biologic DMARDs used
 Combination biologic DMARD - Not recommended
 ↑sed infection risk (tuberculosis and pneumocystis
pneumonia)
 Congestive heart failure (HF)- Relative contraindication

27.  Mechanism of action
 Suppress macrophage and T cell function
 Regression of Inflammatory changes in joint &
new erosions are slowed

28. Etanercept
 Recombinant fusion protein of TNF receptor and
Fc portion of human IgG
 Slows erosive disease progression more than oral
MTX
 Patients with inadequate response to MTX
monotherapy
 Dose – subcutaneous injection of 50mg weekly

29. Infliximab (Remicade)
 Chimeric anti-TNF antibody fused to a human constant - region IgG
 Combination of infliximab and MTX
- Halt progression of joint damage
- Superior to MTX monotherapy
-Improves response and decreases antibody formation against infliximab
 Acute infusion reaction
 Autoantibodies and lupus-like syndrome have also been reported
 Dose – 3-5mg /kg iv every 4-8weeks

30.  Adalimumab
 Recombinant monoclonal anti TNF antibody
 Subcutaneous 40mg every 2weeks
 Combination with Mtx improves response and
decreases antibody formation

31. Certolizumab
 Recombinant humanised antibody Fab fragment
conjugated to a polyethylene glycol (PEG) with
specificity for human TNF α
 Half life of 14 days
 Methotrexate ↓ appearance of anticertolizumab
antibodies
 Used in moderate to severe rheumatoid arthritis

32. Golimumab
 Human monoclonal antibody with high affinity
for soluble and membrane bound TNF α
 Half life – 14 days
 Concomittant use with methotrexate ↑ its
serum levels & ↓anti golimumab antibodies
 Dose – subcutaneous 40mg every 4 weeks
 Used alongwith methotrexate in modertate to
severe rheumatoid arthritis

33. IL -1 antagonist

34. Anakinra
 IL-1 receptor antagonist
 Clinically less effective than TNF inhibitors - used in
cases – failed on one or more DMARDs
 Dose – 100mg subcutaneously
 Main adverse effects
 Local reaction
 Chest infections

35. Abatacept
 Binds to CD80/CD86 receptors on antigen-
presenting cells
 Inhibits interactions between antigen-presenting
cells and T cells
 Used in refractory RA

36. Rituximab
 Monoclonal chimeric antibody
 Binding of rituximab to B cells - Nearly complete
depletion of peripheral B cells
 Useful in patients failing MTX or TNF inhibitors
 Methylprednisolone 100 mg 30 minutes prior to
rituximab to reduce incidence and severity of infusion
reactions

37. Tocilizumab
 Attaches to IL-6 receptors
 Preventing cytokine from interacting with IL-6
receptors
 Moderately to severely active RA who have failed
to respond to one or more anti-TNF biologic
agents
 Monotherapy or in combination with MTX or
another DMARD

38. Corticosteroids

39. Corticosteroids
 Anti-inflammatory and immunosuppressive
properties
 Long term use carries serious disadvantages.
Therefore either
 Low doses (5 -10mg) used to supplement
NSAIDS
 Higher doses are employed for shorter periods in
cases severe systemic manifestation while patient
awaits response from remission inducing drug

40.  Intramuscular route –
 Preferable in nonadherent patients
 Depot forms (triamcinolone acetonide, triamcinolone
hexacetonide, and methylprednisolone acetate)
 Provide 2 to 6 weeks of symptomatic control
 Onset of effect may be delayed for several days

41.  Intra-articular injections
 Depot forms useful - Only a few joints are
involved
 Do not inject any one joint more than two or three
times per year

42. Standard treatment protocol
 Methotrexate
- DMARD of first choice
- Initial treatment of moderate-to-severe
RA
 Failure to achieve adequate improvement with
methotrexate therapy - Consideration for an
effective combination regimen
 Effective combinations include :
 Methotrexate, sulfasalazine, and hydroxychloroquine (triple
therapy)
 Methotrexate and leflunomide
 Methotrexate plus a biological

43.  Combination of methotrexate and an anti-TNF
agent
 Randomized, controlled trials to be superior
to methotrexate alone
 Reducing signs and symptoms of disease
 For retarding progression of structural joint
damage.

44.  Some patients may not respond to an anti-TNF
drug or be intolerant of its side effects. Initial
responders to an anti-TNF agent that later
worsen may benefit from switching to another
anti-TNF agent.
 Other biologicals - abatacept and rituximab, may also
be considered for treatment - disease refractory to
anti-TNF therapy.
 Addition of abatacept or rituximab to background
methotrexate therapy –
 In well-designed clinical trials
 Effective for reducing signs and symptoms of joint
inflammation and slowing radiographic progression of
disease.

45. OTHER MANAGEMENT
CONSIDERATIONS
Pregnancy
 Up to 75% of female RA patients - overall improvement in
symptoms - during pregnancy
 Will often flare post-delivery
 Flares during pregnancy - Low doses of prednisone ;
hydroxychloroquine and sulfasalazine (probably safest
DMARDs to use during pregnancy)
 Methotrexate and leflunomide - Contraindicated during
pregnancy (due to their teratogenicity in animals and
humans)
 Experience with biologic agents - Insufficient to make specific
recommendations for their use during pregnancy.

46. Elderly Patients
 RA - Up to one-third of patients after age of 60
 Recognized that older individuals - Receive
less aggressive treatment due to concerns
about increased risks of drug toxicity
 Studies suggest - Conventional DMARDs as
well as biologic agents - Equally effective and
safe in younger and older patients

47.  Due to comorbidities - ↑ risk of infection
 Aging –
 ↓ in renal function
 may raise risk for side effects from NSAIDs and
some DMARDS, such as methotrexate
Methotrexate - not prescribed for patients
with a serum creatinine greater than 2
mg/dl

48. NON PHARMACOLOGIC
THERAPY
 Adequate rest
 Weight reduction - if obese
 Occupational therapy
 Physical therapy
 Use of assistive devices may improve symptoms and help
maintain joint function
 Patients with severe disease may benefit from surgical
procedures such as
 Teno synovectomy
 Tendon repair
 Joint replacements
 Patient education about disease and benefits and limitations
of drug therapy is important

49. Summary
 NSAIDS –
 Provide symtomatic relief
 Used in mild or early cases
 DMARDs
 Retard disease progression
 To be started as soon as diagnosis RA confirmed
 In early or mild cases of RA benefits should be
weighed agaist adverse effects
 Corticosteroids
 Low doses – to supplement NSAIDs
 High doses – for systemic manifestation

50. References
 Goodman & Gilman’s The Pharmacological
Basis of Therapeutics 12th edition
 Katzung Basic and Clinical Pharmacology 12th
edition
 Harrison's Principles of Internal Medicine, 18e

52. When single-
DMARD treatment
is unsuccessful -
Combination
therapy
Recommended
combinations
include
• MTX plus
hydroxychloroquine
• MTX plus leflunomide
• MTX plus sulfasalazine
• MTX plus
hydroxychloroquine
plus sulfasalazine

53. Algorithm for treatment of rheumatoid
arthritis in early disease.

54.  DMARDs - less frequently used include
 Anakinra (IL-1 receptor antagonist)
 Azathioprine
 Penicillamine
 Gold salts (including auranofin)
 Minocycline
 Cyclosporine
 Cyclophosphamide
Less efficacy or higher toxicity, or both

55. Algorithm for treatment of rheumatoid arthritis
in established disease (>6 months).

56. Biologic DMARDs include
 Anti-TNF agents
 Etanercept
 Infliximab
 Adalimumab
 Certolizumab
 Golimumab
 Costimulation modulator - Abatacept
 IL-6 receptor antagonist
 Tocilizumab
 Rituximab
 Biologic DMARDs - Proven effective for patients failing treatment with non
biologic DMARDs