Treatment of Rheumatoid arthritis

1. TREATMENT OF
RHEUMATOID ARTHRITIS
(RA)
Pravin Wahane
B.J.G.M.C. Pune

2. INTRODUCTION
• Chronic, systemic, inflammatory,
autoimmune
• Primary target is the synovial tissue
• Characterized by joint erosions and
destruction

3. EPIDEMIOLOGY
• Commonest inflammatory joint disease seen
in practice
• Affects around .8% of world’s and about
1% of Indian population
• Commoner in women by a ratio of 3:1
• Usually starts in 3rd to 5th decade of life
• Associated mortality

4. AETIOLOGY
• Multifactorial
• Genetic predisposition and shared epitope
hypothesis
• Role of infections
• Molecular mimicry

6. TREATMENT PARADIGMS
PAST
Traditional pyramidal approach;Go slow, go low
(empirical)
PRESENT Early and universal use of DMARDs (Disease
modifying anti rheumatic drugs)
often in combination (evidence based)
FUTURE DMARDs + Biological agents
(mechanism based)

7. IMPORTANCE OF EARLY
DIAGNOSIS AND
TREATMENT
• Joint damage is an early phenomenon
• It is largely irreversible
• Duration of the disease is inversely
proportional to outcome and response

8. ACR CRITERIA FOR
DIAGNOSIS OF
RHEUMATOID ARTHRITIS
• Morning stiffness(lasting at least 1 hour)
• Arthritis in 3 or more joint areas (soft tissue
swelling or effusion observed by physician)
• Arthritis of hand joints(wrist,PIP,MCP joints)
• Symmetric arthritis
• Rheumatoid nodules
• Rheumatoid factors in serum
• Radiological changes(erosions or periarticular
bony calcifications on hand and wrist radiographs)

9. OTHER AIDS TO
DIAGNOSIS
• Elevated levels of serum rheumatoid factors
• Radiographic changes
• Serum antibodies like antibodies to CCP

10. SEVERITY ASSESSMENT
• Duration of morning stiffness
• Tender and swollen joint count
• Observer and patient assessment
• VAS for pain
• Disease activity score (DAS)

11. SEVERITY ASSESSMENT
DAS
• Most widely employed
• Requires 28 tender joint count, 28 swollen
joint count, ESR and general health
assessment by the patient
• Can range from 0-9.4
• Remission
• Meaningful change

12. POOR PROGNOSTIC
FACTORS
• High tender/swollen joint count
• Early age of onset
• High titres of RF, ESR and CRP
• Erosions on hand X-rays
• Presence of CCP antibodies

13. MEASUREMENTS OF
RESPONSE
ACR 20 Response :
A decrease of at least 20% in both the number
of tender and swollen joints along with 20% reduction
in at least three of the following:
,
Patient s assessment of disease status
,
Patient s assessment of pain
,
Patient s assessment of physical function
,
Physician s assessment of disease status
C-reactive protein level

14. CLASSIFICATION OF
DRUGS
• NSAIDs ( Non steroidal antiinflammatory
drugs)
• Corticosteroids
• DMARDs
• Biological response modifiers (BRMs)

15. BROAD ALGORITHM

16. Diagnosis establishment
Assessment of baseline disease activity and damage
Prognosis estimation
NSAIDs
DMARD as per severity
Consider local or systemic corticosteroids
Response-continue
Response- continue
No response
Add Methotrexate if not already used
Parenteral MTX if oral MTX used
No response
Add other DMARDs
Add BRMs

17. NSAIDs IN RA
• Integral part of initial therapy
• Buy time and offer symptomatic benefit
• ‘Adjuncts to’ and not ‘substitutes for’
DMARDs

18. NSAIDs IN RA
• Combination of NSAIDs
• Adverse effects
• COX-2 inhibitors
• Measures to control adverse effects

19. CORTICOSTEROIDS IN RA
• Retard the rate of joint destruction and
relieve synovitis in low doses
• Mild disease modifying potential
• Adverse effects and their prevention

20. CORTICOSTEROIDS IN RA
• Bridge therapy for 8-12 weeks
• Treatment of rheumatic flares
• For rheumatic vasculitis and interstitial lung
disease
• Intra-articularly in recalcitrant joints

21. DMARDs IN RA
• Step up approach
• Step down approach
• Saw tooth approach
• Parallel approach

22. DMARDs IN RA
FREQUENTLY
USED
INFREQUENTLY
USED
•
• Methotrexate
•
• Hydroxychloroquine •
• Sulphasalazine
•
• Leflunomide
•
•
Chloroquine
Gold
Cyclosporin A
Levamisole
D-penicillamine
Minocycline

23. METHOTREXATE
• Anchor of treatment
• Acts by inhibiting dihydrofolate reductase,
thymidylate synthetase and
aminoimidazolecarboxamide
• Most economical, best tolerated and with
highest rate of retention

24. METHOTREXATE
• Initial and maintenance dose
• Duration of treatment
• Treatment failure

25. METHOTREXATE
• Adverse effects
• Their prevention
• Contraindication

26. HYDROXYCHLOROQUINE
• Suggested mechanisms involve suppression
of T lymphocyte responses to mitogens,
reduced chemotaxis, free radical trapping
• Extensively bound to tissues specially to
melanin containing ones
• Place in treatment of RA

27. HYDROXYCHLOROQUINE
• Usual dosage
• Adverse effects

28. SULFASALAZINE
• Sulfapyridine is the active moiety
• Acts by inhibition of proinflammatory
cytokines and transcription factors
• Usually used as an add on drug
• Also useful in juvenile arthritis and
ankylosing spondylitis

29. SULFASALAZINE
• Adverse effects
• Use in pregnancy

30. LEFLUNOMIDE
• New DMARD
• Isoxazole derivative
• Acts by competitive inhibition of
Dihydroorotate dehydrogenase

31. LEFLUNOMIDE
Dihydroorotate
Uridine
monophosphate
Orotate
Early signals
IL2, NFAT
Ca influx
+
Go
_
G1
Sensors of Ribon. Levels
p53, cyclin D & E
S
G2
M

32. OTHER ACTIONS
• Inhibition of Tyrosine kinase
• Inhibition of NF-kB dependant transcription
• Reduction in levels of IL-6, matrix
metalloproteinases and prostaglandin E

33. PROPERTIES
• Prodrug
• Highly protein bound with long t ½
• Undergoes extensive enterohepatic
circulation
• Inhibits CYP2C9

34. USE IN RA
• Found to be as efficacious as Sulfasalazine
and MTX
• Slows radiographic progression as
compared to placebo
• Alternative agent in face of MTX
intolerance in the dose of 20 mg/day
• Combination of MTX and Leflunomide

35. PREGNANCY PROTOCOL
• Leflunomide in fetopathic and teratogenic
• Should be discontinued before pregnancy
• Emergency drug washout with oral
Cholestyramine 8gm thrice daily for 11
days

36. ADVERSE EFFECTS
• Reversible elevation in liver enzymes in 24% of patients
• Risk of severe liver injury is small and
acceptable
• Weight loss
• Diarrhea
• Alopecia
• Hypertension
• others

37. COMBINATION OF
DMARDs
• Better than monotherapy in inducing
remission
• Cost effective in long term
• Not necessarily more toxic
• MTX +Leflunomide
• MTX+Sulfasalazine +Hydroxychloroquine

38. DMARDs IN SPECIAL
SITUATIONS

39. Contraindicated
Indicated
Pregnancy
MTX, Leflunomide
Sulfasalazine,Steroids
HCQS, NSAIDs
Lactation
do
Cyclosporin
do
Gold salts
Liver
disease
MTX, Leflunomide,
NSAIDs,
Sulfasalazine
HCQS and Gold salts
Renal
disease
NSAIDs, MTX- dose
Gold
HCQS, Sulafasalazine
Lung disease MTX - caution
Leflunomide, HCQS
and Sulfasalazine

40. BRMs IN RA
• Integration of molecular biology with
bedside medicine
• Genetically engineered products
• Modulate a specific aspect of underlying
autoimmune process
• Therapeutic effect involves downregulation
of proinflammatory cytokines and
occupancy of their receptors

41. BRMs IN RA
• Soluble TNF α receptor – Etanercept
• Anti TNF α antibodies - Infliximab,
Adalimumab
• IL1 receptor antagonist – Anakinra

42. ETANERCEPT
• Soluble TNF receptor fusion protein
• Composed of soluble ligand binding portion
of type2 TNF receptor linked to Fc portion
of human IgG
• Has affinity with both TNF α and β and
binds to them before they can bind to their
receptors

43. ETANERCEPT
• Given by SC route
• Dosage
• Bioavailability-60%
• t ½ - 50 hrs

44. ETANERCEPT IN RA
• Better and faster ACR response rates as
compared to placebo
• Rapidity is dose dependent
• Beneficial in patients who have an
inadequate response to MTX
• Approved for use as monotherapy

45. INFLIXIMAB
• Chimeric IgG anti-TNF-α antibody
• Binds to both soluble and membrane bound
TNF-α
• First anti-TNF-α agent used

46. INFLIXIMAB- EFFECTS
• Reduces serum conc. of IL6
• Reduces serum conc. of ICAM-1 and E
selectin
• Reduces vascular endothelial growth factor
• Increases expression of TNF receptors

47. INFLIXIMAB
• Half life about 9 days
• 3 mg/kg by IV infusion at 0, 2 and 6 weeks
followed by every 8 weeks
• Single IV dose confers rapid improvement
• Has been found to be effective as compared
to placebo but monotherapy associated with
loss of efficacy
• Can only be used in combination with MTX
• Other uses

48. ADALIMUMAB
• Recombinant human IgG monoclonal antiTNF-α antibody (1330 amino acids)
• Not only causes impaired cytokine binding
but also lyses cells expressing surface
TNF-α

49. ADALIMUMAB
• Given by SC route . Dose 40 mg SC weekly
• t ½ 2 weeks
• Bioavailability 64%

50. ADALIMUMAB IN RA
• Has shown better ACR response rates as
compared to placebo
• Appears to have additive effect with MTX
• Inhibits progression of structural joint
damage
• Dose adjustment with MTX

51. ADRs OF TNF
ANTAGONISTS

52. INFECTIONS
• Definite risk of opportunistic infections
such as tuberculosis and histoplasmosis
• Max risk with Infliximab
• Tuberculosis occurs due to reactivation of
old latent infection
• Occurs within first 2-5 months of therapy
• Importance of screening procedures

53. MALIGNANT DISEASES
• Increased incidence of lymphoma but
causal association lacking
• No evidence of any other malignancy

54. INJECTION SITE AND
INFUSION REACTIONS
• Minor redness and itching for few days
after receiving Etanercept and Adalimumab
• Headache and nausea after Infliximab
• Urticaria and anaphylaxis in 2% patients
after Infliximab

55. IMMUNE RESPONSES
• Etanercept is least immunogenic and
antibodies found only in 3% patients
• Human chimeric antibodies develop in a
majority of patients taking Infliximab
• Combination with MTX blunts the
autoimmune response
• Antibodies to Adalimumab found in 12%
patients receiving monotherapy but only in
1% of those receiving MTX combinatuion

56. DEMYELINATING
SYNDROMES
• Reports of exacerbation of quiescent
multiple sclerosis in patients taking
Etanercept and Infliximab
• Causal relationship not established

57. IL-1 AND RECEPTOR
ANTAGONISTS
• Role of IL-1 in immune and inflammatory
process
• IL-1 receptor antagonist(IL-1Ra)
• Dynamic balance

58. ANAKINRA
• It is recombinant IL-1Ra
• Binds competitively to IL-R type 1
• Given 100 mg/day SC
• Bioavailability-95% ; t ½ 4-6 hrs
• Elimination by renal clearance

59. ANAKINRA
• Has been found to be effective as compared
to placebo both in monotherapy and
combination with MTX
• Slows the rate of joint damage
• Useful in patients who have no response or
fail to tolerate DMARDs and other BRMs

60. ANAKINRA
• Theoritical possibility of synergistic action
with TNF antagonists but not substantiated
by studies
• Well tolerated with MTX but a small
fraction can develop reversible neutropenia
• Contraindicated in presence of active
infections
• Daily injections have limited its role

61. BRMs IN RA
• Indicated in resistant RA with active disease
(DAS >5.1)
• Defined as failure of response to at least 2
DMARDs ( one should be MTX) used in
optimal doses for at least 6 months
• Generally have rapid onset of response
• Should be withdrawan in case of advent of
adverse effects or lack of effect(DAS
improvement <1.2 at >3 months)
• Major deterrent to their use is cost

62. INITIAL TREATMENT
Oral MTX 7.5-15mg per week +/- 5-7.5 mg Prednisone per day
5 mg increments in dose every month to a max of 20-30 mg per week
Switch to subcutaneous injections
DMARD combination
New concept- Induction therapy with Etanercept which has been
found to rapidly suppress disease activity

63. ESTABLISHED RA
Maximal MTX dose
2-3 months
Add Sulfasalazine, Hydroxychloroquine or both but not Cyclosporin
3 months
Add Leflunomide to MTX
1 year after diagnosis
TNF inhibitors

64. COEXISTING ILLNESSES
• Infections
• Osteoporosis
• Cardiovascular disease

65. INFECTIONS
• Doubling of the risk of infection and degree
of increase correlates with severity
• Possible role of corticosteroids and TNF
inhibitors
• Regular Influenza and Pneumococcal
vaccination ( start before DMARD)
• Prescreen and follow up for TB

66. OSTEOPOROSIS
• Incidence of osteoporosis is doubled
• Base line bone density studies
• Bisphosphonate therapy

67. FUTURE STRATEGIES
• B cell depletion therapy using Rituximab
• Inhibition of IL-6
• Inhibition of IL-18
• Costimulation block

68. RITUXIMAB
• Chimeric monoclonal IgG anti CD20 antibody
• Has shown significant efficacy comparable to
TNF inhibitors

69. RITUXIMAB-DOSAGE
• Given by slow infusion
• Two doses of 1 gm each 1 week apart
• Methyl Prednisolone as premedication on the
day of dosing
• Effects last at least 6 weeks
• Monotherapy in RF +ve patients
• No benefit of combining with MTX

70. ADVERSE EFFECTS
• Pricking sensation in the throat at the time of
first infusion
• Increased risk of lower airway infections
• Transfusion reactions

71. IL-6
• Pleiotropic cytokine, glycoprotein in nature
• Various names
• Produced by a variety of immunocytes and
mesenchymal cells
• Binds to cell surface or soluble receptor
• IL-6/IL-6R complex binds to gp 130 on cell
surface and leads to effects

72. FUNCTIONS OF IL-6
• Stimulation of B cells
• Proliferation and differentiation of T cells
• Differentiation of osteoclasts and increased
proteoglycan breakdown
• Pyrogenic and weight loss
• Paradoxically suppresses IL-1 and TNF-α

73. IL-6 IN RA
• Implicated in joint damage and systemic
manifestations of disease
• IL-6 knockout mice
• Results of SC IL-6

74. ANTAGONISTS OF IL-6
•In animal models
•In human studies
Rapid improvement with 10 days treatment
in initial studies (10 mg/kg IV OD)
In subsequent studies, found to be effective
after 1 wk and sustained effect till 8 wks
Optimum dose- 8 mg/kg
Combination with MTX found to be better
than monotherapy with either drug

75. INTERLEUKIN - 18
• Belongs to IL1 superfamily
• Major function is induction of INF-γ
• Also induces T- helper cells as also other
inflammatory cytokines
• Increased levels are seen in patients of RA
• IL-18BP is produced endogenously and
counters IL-18

76. ROLE OF IL-18 AND ITS
ANTIBODY
Antimurine IL-18 antibody
Suppresses swelling by 60% and reduces TNFα
and IL-1 levels when given to Rabbits with
Streptococcal cell wall induced arthritis
IL-18 when given to Mice immunized with type II
collagen, increases the erosive and inflammatory
component of arthritis

77. ROLE OF IL-18BP
Reduces the clinical severity of the disease in Mice
having CIA and causes a reduction in the levels of
circulating cartilage matrix protein
Murine IL-18BP fused with Fc portion of murine IgG
Has been found to reduce histological severity

78. COSTIMULATION
BLOCKERS
• Requirement of dual signal for T-cell
activation
• CTLA4 – constitutively expressed protein
on T cell surface

79. CTLA4-Ig
• It is a soluble antigen immunoglobulin
fusion protein
• Consists of extracellular domain of human
CTLA4 and Fc portion of human IgG

80. CTLA4-Ig IN RA
• Found to induce long term graft survival in
rodent models
• In phase-II trails – combination of
CTLA4Ig and MTX compared with MTX
monotherapy
• Combination showed ACR 20 response in
60% patients as compared to 35.3% in
monotherapy group

81. OTHER AGENTS
• Pegylated soluble TNF-α receptor
antagonist
• Agents that trap cytokines
• Interleukin 15 blockers
• Agents that prevent the cleavage of human
compliment component C5
• Agents that inhibit adhesion molecules