Musculoskeletal disorders: Rheumatoid arthritis- Diagnosis, epidemiology, pathogenesis, treatment goal, counselling

1. Rheumatoid
Arthritis

2. Presentation Outlines:
 Introduction
 Epidemiology
 Pathogenesis
 Clinical manifestation
 Diagnosis
 Treatment
 Conclusion

4. INTRODUCTION
R A is a chronic systemic inflammatory
disorder that may affect many tissues &
organs-skin, blood vessel, heart, lungs,
& muscles -but principally attacks the
joints, producing a non-suppurative,
proliferative and inflammatory synovitis.

6. • The disease if not treated early, leads to
progressive joint deformity & increased
morbidity and mortality.
• RA is a potentially fatal illness, with
mortality increased 2 folds & an average
decrease in life expectancy of 7-10 yrs.
• Infections, renal impairment, CVD,
lymphomas increases co-morbidity &
mortality.

8. Presentation Outlines:
 Introduction
 Epidemiology
 Pathogenesis
 Clinical manifestation
 Diagnosis
 Treatment
 Conclusion

9. Epidemiology
• RA is one of the most common autoimmune
diseases, with a prevalence of approx 1%.
• It is more common in females than in males (3:1)
• The onset is most common in the age group between
30 and 50 years.---Slightly older in men

10. • 5% Women & 3% men over the
age of 65 yrs affected by RA.
• RA affects young children and its
classification and treatment differs
slightly from adults.
• In India, the prevalence of RA is
estimated to be 0.7% which is higher
than the global prevalence of 0.46%

13. Presentation Outlines:
 Introduction
 Epidemiology
 Pathogenesis
 Clinical manifestation
 Diagnosis
 Treatment
 Conclusion

14. Pathogenesis
• RA is an autoimmune disease triggered
by exposure of a genetically susceptible
host to an unknown antigen.
• Activation of CD4+ helper T cells &
other lymphocytes, & the local release
of inflammatory mediators & cytokines
that ultimately destroys the joint.

16. • The cause of RA remains unclear
with hormonal, genetic and
environmental factors playing a key
role.
• Genetic factors contribute 53-65% of
the risk of development of disease

17. Key consideration
1) The nature of the autoimmune
reaction,
2) The mediators of the tissue injury,
3) Genetic susceptibility, and
4) The arthritogenic antigen(s).

19. 1 RA CD4+ T cells
& B lymphocytes.
+
cytokines (central mediators
of the synovial reaction)
&
B cells activation
joint destruction

20. 2 Joint injury is very important.
• Cytokines plays a major role.
• i.e. TNF & IL-1 produced by
macrophages & synovial lining cells
different inflammatory mediators
(i.e. PG) ,matrix metalloproteinases
cartilage destruction

22. • Activated T cells & synovial fibroblast
Receptor Activator for Nuclar factor fB
Ligand ( RANKL)
Osteoclasts (a large multinucleate
bone cell which absorbs bone during growth & healing)
Joint destruction
 These series of event is leads to progressive joint
destruction

23. • Hyperplastic synovium  adherent to
& articular surface
PANNUS
( Irreversible cartilage destruction & erosion
of subchondral bone )

25. 3 Genetically susceptibility is a significant
component of the development of RA.
• RA is highly present in monozygotic twins
and well-defined familial predisposition.
• Multiple gene loci are believed to be
responsible for susceptibility to the
disease, but most of these have not been
identified yet.

26. • 1 susceptibility that is in the class ІІ HLA
locus, & specifically region of 4 amino
acids located in the antigen binding cleft
that is shared in the HLA DRBI*0401 &
0404 alleles.
• Thus formed HLA-DR allele may bind and
display the arthritogenic antigen to T
cells, however there is no evidence for
support this idea.

27. 4 trigger
• Antigens autoimmunity &
increase reaction are not known.
• There has been great interest in
exploring microbial antigens as the
initiating triggers.
• But no firm evidence has definitively
identified a microbial organism as an
etiologic agent in RA.

30. Presentation Outlines:
 Introduction
 Epidemiology
Pathogenesis
 Clinical manifestation
 Diagnosis
 Treatment
 Conclusion

31. Clinical Presentation
• Fatigue
• Low-grade fever
• Loss of appetite
• Weakness & joint pain
• Stiffness & myalgias may precede
development of synovitis.

33. Extra- articular features of RA
• Amyloidosis
• Carpal Tunnel Syndrome
• Episcleritis
• Feltre's syndrome
• Fever
• Lymphadenopathy
• Osteoporosis
• Pericarditis
• Scleritis
• Vasculitis
• Pleural and pericardial effusion.

35. Presentation Outlines:
 Introduction
 Epidemiology
Pathogenesis
 Clinical manifestation
 Diagnosis
 Treatment
 Conclusion

36. Diagnosis
The American Rheumatism Association
(ARA) criteria for classification of
Rheumatoid Arthritis include
• The 1987 revised ARA/ACR criteria for
the classification of rheumatoid
arthritis.
1. Morning stiffness
2. Arthritis of 3 or more joint areas

37. 3. Arthritis of hand joints
4. Symmetric arthritis
5. Rheumatoid nodules
6. Serum Rheumatoid factor
7. Radiographic changes

38. Presentation Outlines:
 Introduction
 Epidemiology
Pathogenesis
 Clinical manifestation
 Diagnosis
 Treatment
 Conclusion

39.  The goals of management of RA are
to
• relieve pain and inflammation
• relieve joint destruction
• preserve or improve a patient’s
functional ability,
• maintain a patient’s normal life style.

40. Management
1. Non-pharmacological therapy
• Physiotherapy plays a very important
role
• Heat, cold & electrotherapy help to
reduce pain and swelling.
• Patient education about the disease
2. Pharmacotherapy

42. Pharmacotherapy
• Specific treatment is depends on
 Patient joint function,
 Degree of disease activity,
 Age,
 Gender,
 Occupation,
 Family responsibilities,
 Drug costs,
 Results of previous therapy.
• The old standard for treatment of RA,
known as the “pyramid approach”.

43. Experimental
Drugs or Procedures
& cytotoxic agents
Penicillamine,
Methotrexate, Azathiprine
Hydroxychloroquine, gold
Education, rest, Exercise; Social services;
salicylates or other NSAIDs

44. • The pyramid approach has not made an
impact on functional, clinical, or radio
logic evidence of disease progression.
• NSAIDs are associated with significant
toxicities.
• DMARDs (Disease Modifying Anti-
Rheumatic Drugs) are not as toxic as
once believed.
• NSAIDs do not prevent or slow joint
destruction.

48. • A DMARD should be started with in the
first 3 months of onset of symptoms of
RA.
• Early introduction of DMARD results in a
more favorable outcome & can reduce
mortality compared to people with out
the disease.

49. • First-line DMARDs include:
• methotrexate,
• hydroxychloroquine,
• sulfasalazine,
• leflunomide.

50. • The order of agent selection is not
clearly defined.
• Hydroxychloroquine / sulfasalazine may
be used initially in mild disease.
• Methotrexate is often chosen initially in
more severe cases. It is economically
cheaper than biologic agent.
• Leflunomide appears to have long-term
efficacy similar to methotrexate.

51. • Biologic agents have proven for patients
who fail treatment with other DMARDs.
• Infliximab should be given in
combination with methotrexate.
• When single DMARD fails to achieve
goal that time combination therapy may
be beneficial.
• The combinations of
(1) cyclosporine + methotrexate.
(2) methotrexate + sulfasalazine &
hydroxychloroquine have been shown to
be particularly effective.

52. • DMARDs that are less frequently used
include Azathiprine, Penicillamine, gold
salts (including auranofin), minocycline,
cyclosporine & cyclophasphamide.
• These agents have either fewer
efficacies or high toxicity, or both.

53. • NSAIDs, corticosteroids may be used for
symptomatic relief if needed.
• These are provide relatively rapid
improvement compared with DMARDs,
which may take weeks to months before
benefit seen.
• However, NSAIDs have no impact on
disease progression, & corticosteroids
have the potential for long-term
complications like Osteoporosis, adrenal
insufficiency, hyperlipidemia,
ophthalmological effects, growth
suppression.

55. Simple analgesics:
• Paracetamol, its combinations with &
Dihydrocodeine are all useful for
simple pain relief.
• These are not alters the disease, but
can be used in the management of
both acute and late stages of the
disease.

56. Non-steroidal anti-inflammatory drugs
(NSAIDs)
• NSAIDs act primarily by inhibiting
prostaglandin synthesis, & produces
anti-inflammatory effect.
• These agents possess both analgesics
and anti-inflammatory
• These agents replace the use of high
dose aspirin, as they are less toxic,
longer acting & have better adherence.

57. MOA of NSAIDs
Cyclooxygenase
(COX) Prostaglandins
ADR:
GIT. Minor nausea, dyspepsia, anorexia, &
abdominal pain, are common up to 60% of
patients.
 GI bleeding, occur in 1.5% to 4% of
patients per year.
N
S
A
I
D

58. Drug Dosage & Frequency Maximum dose
(Mg/d)
Carboxylic acids
Aspirin
325-650 mg for pain,
3600mg/d in divided dose
for antiinflammatory
3600
Acetic acids
Etodolac
Diclofenac
800-1200mg/day
100-150mg/day
25mg tid or bid
1200
200
Propionic acids
Ibuprofen
1200-3200mg/day 3200
Fenamates
Mefenamic acid
Meclofenamate
250mg qid
200-400mg/day
1000
200
Oxicams
Piroxicam
10-20mg/day 20
Coxibs
Celecoxib
Valdecoxib
100mg bd or 200 mg od
10mg od
100
10

59. Disease modifying anti rheumatic drugs
(DMARDs)
• Early newly diagnosed RA patient is a
candidate for DMARD therapy, which
should be started with in 3 months of
diagnosis.
• All the DMARDs possess a slow onset
of action, with response to treatment
usually expected with in 4-6 months.

60. Mechanism of action of DMARDs
• DMARDs  reduce the activity of
inflammatory cytokines
Ex: Methotrexate
Leflunomide
Hydroxychloroquine
Sulfasalazine
Penicillamine
Gold
Corticosteroids
Biological agents

61. Methotrexate
It is the 1st drug of choice used by
many rheumatologists.
 It is probably the most effective DMARD.
 It has a relatively rapid onset of action of 4-6
weekly doses.
 It is commonly used in patients with
moderate to severe disease, especially in those
with poor prognosis.
 It has a relatively high response rate of 40-
50% & has been shown to improve quality of
life & reduce joint destruction.

62. Leflunomide
• It is a new, oral DMARD for
the treatment of RA.
• It inhibits pyrimidine synthesis, leading to a
decrease in lymphocytes proliferation &
modulation of anti-inflammation.
• It is used when the current available drugs fails
to relieve the signs & symptoms because of its
serious adverse effects.
• Post marketing surveillance has resulted in the
reporting of more than 130 severe liver-related
adverse events, including 12 liver related deaths
like due to this drug.

63. Hydroxychloroquine:
• HCQ & other antimalarials are the
less toxic of all DMARDs.
• These are used in less severe forms
of the disease.
• This can be used with other DMARDs.

64. Sulfasalazine:
• It is a prodrug, which is cleaved by
bacteria in the colon into sulfa pyridine &
5-amino salicylic acid.
• It is believed that the sulfa pyridine moiety
is responsible for anti-rheumatic
properties.
• However the exact mechanism is not
clearly known.
• It can be used in long-term therapy.
Because of its low serious adverse effects.

65. Penicillamine:
• There is not evidence that
Penicillamine reduces joint erosions.
• Penicillamine is not often used for
the treatment of progressive RA
because of a lengthy dose titration.
• For dosing, “go low, go slow” is
recommended for dosing
Penicillamine.

66. Gold:
• Gold:
• 2 parenteral gold preparations are
available. Gold sodium thiomalate, an
aqueous solution and Aurothio glucose
or an oil suspension.
• Orally available as Auronofin.
• Gold sodium thiomalate is easier to
administer, but it is associated with
more frequent side effects compared
with aurothioglucose (less risk of
nephrotoxicity).

67. Corticosteroids
•In a low dose it have
disease-modifying
properties.
• They interfere with antigen presentation to
T-lymphocytes, inhibit prostaglandin &
leukotriene synthesis.
• It also impairs cell migration & cause
redistribution of monocyte, lymphocytes &
neutrophils is thus by producing inflammatory &
autoimmune response.

69. • Systemic corticosteroids have long
been used in the management of RA.
• Once commenced systemic
corticosteroids difficulty to with draw.
• To minimize the side effect, a daily
maintenance dose of 7.5mg of
prednisolone or less should be used,
given as a single dose.

71. DMARDs dose
& regimens,
performance &
their action

72. DRUG DOSE &
REGIMENS
PERFORMANCE ACTION
1.Methotrexate 7.5 mg /Wk PO Rapid response
in 1-2 months
Antimetobolite
2.Sulfasalazine 1g tid/bid ,Po Rapid response
in 1-2 months
Anti-
inflammatory
3.Hydroxychloroq
uine
200mg orally, i.e.
<6mg/kg/day
Response in 2-4
months
Inhibit the
locomotion of
neutrophils, &
chemotaxis of
eosinophils.impai
rs complement
dependent
Ag-Ab reaction
4.Leflunomide 10-2-mg orally,
once daily
Efficacy
comparable with
methotrexate
Anti-
inflammatory &
autoimmune
modulatory
properties
5.Azathiprine Orally 1.5-
2.5mg.kg/day
May have steroid
sparing effect
Immunosuppress
ant agent

73. DRUG DOSE &
REGIMENS
PERFORMANCE ACTION
6.Gold
Auranofin
Gold thiomalate
PO: 3mg od/ bd
IM: 10mg test
dose, then wkly
dosing 25-50mg,
after response may
increase dosing
interval
Excellent response
over 3-12 months
in 20-30% only.
Half sustain this
improvement after
1 yr.
Unknown may
decrease PG
synthesis or may
alter cellular
mechanism by
inhibiting
sulfhydrys system
7. Penicillamine 250-750mg orally
in divided doses
Similar pattern of
response to gold,
( i.e., 3-6 months)
It depresses
circulating IgM
rheumatoid factor,
depresses T-cell
but B-cell activity
8.Prednisolone
/prednisone
5-7.5mg orally in
the morning
Rapid reduction
(days)in synovitis
pain & stiffness;
Anti-inflammatory
effect
9. Cyclosporin 2.5-3mg/kg/day
orally
Response in 3-6
months
Immunosuppressa
nt agent
10.Cyclophosphami
de
1-2mg/kg/day
orally
It is used in the
management of
rheumatoid
vacuities
Cytotoxic agent

74. DMARDs adverse effect
and
their monitoring

75. Drugs (pregnancy category) Common adverse effect Monitoring
1.Methotrexate (X) GI symptoms, rash, mouth
ulcers, alopecia,
Myelosuppression; hepatic
fibrosis or cirrhosis; pulmonary
infiltrates or fibrosis
FBC fortnightly for 12 wks
then monthly.
LFTs monthly
2.Sulfasalazine (B) Rashes; GI upset; liver function
abnormalities;
Myelosuppression and
hemolytic anemia (rare)
3.Hydroxychloroquine(C) Drug deposition in cornea;
macular damage (rare)
Fundal examination & fields by
ophthalmologist at baseline
then every 6 months
4.Leflunomide (X) Diarrhoea; alopecia;
contraindicated in women of
child- bearing potential
FBC, PLT & LFTs at baseline
then every 4 to 8 weeks

77. 5.Gold
Auranofin (C)
Gold thiomalate
Pruritis & mouth ulcers
commonest; proteinuria &
rarely nephrotic syndrome;
Myelosuppression; neutropenia
and thrombocytopenia
(commonest) aplasia (rare)
FBC, PLT & U/A at baseline
then every 1 to 2 wks for 20
wks then with each
administration
7.Prednisolone/prednisone
(D)
Weight gain; fat redistribution;
unmasking diabetes; muscle
wasting and weakness
hypertension; cataracts;
osteoporosis;
Clinical monitoring for wt
gain, HTN glycosuria; monitor
& prophylaxis against
osteoporosis beware too rapid
cessation after rapid cessation
after therapy because of
adrenal cortex suppression

78. 7. Penicillamine (D) Rashes; mouth ulcers; metallic
taste Myelosuppression;
proteinuria
FBC, PLT & U/A at baseline
then every 2wk until dose is
stable then every 1-3 month.
8.Azathiprine (D) Hepatitis, cholestatic jaundice,
myelosupression
FBC,U&E & LFTs fortnightly
for 2-3 mths, then 1-2 mthly
9.cyclosporin (C) Hypertension; impaired renal
function; paresthesia; hirsutism
FBC< PLT & U&E at baseline
then mthly
10.Cyclophosphamide (D) Alopecia; nausea and vomiting;
headache skin rash
FBC with PLT, BUN, UA&SE
& creatinine

79. Biologic agents
EX:
 Etanercept
 Infliximab
 Adlimunab
 Anakinara

80. • These are a genetically engineered
protein molecules that block pro-
inflammatory cytokines.
• TNF is a pro-inflammatory mediator
that contributes to the pathogenesis of
synovitis & joint destruction in RA.
• This discovery of TNF led to the
development of TNF blockade therapy.

81. Advantage:
They have not toxicity that requires
laboratory monitoring.
Disadvantages:
 More economic to use.
A small increased risk for infection like
TB. So Tuberculin skin testing is
recommended before treatment with
these agents.
Infliximab & Etanercept are C/I in-
patient with CVS disease like CHF,
because it may exacerbate the
symptoms.

83. Etanercept
• It is a fusion protein consisting of 2 p75
soluble TNF receptor linked to an Fc
fragment of human IgG.
• The MOA often is competitive inhibition
of TNF, binding to cell surface receptors &
preventing TNF mediated cellular
response.

84. Etanercept
• According to many clinical trials, patients who failed to
DMARDs a good response were shown when Etanercept
used up to 60-70%.
• It has been shown in clinical trials to slow erosive
disease progression to a greater degree than
• Oral MTX therapy in-patient with inadequate response to
MTX monotherapy.
• The commonly observed adverse effect is UTI
Dose : 25mg twice
wkly / 50mg once
wkly  SC

86. Infliximab
It is a chimeric antibody containing portions of
mouse & human IgG1.
An anti-TNF Ab was created by exposing mice to
human TNF.
The binding portion of that antibody was fused to
a human constant region IgG1 to reduce the
antigenecity of the foreign protein.

87. Infliximab
• This Ab, when injected in humans, binds to TNF
& prevents its interaction with TNF ® on
inflammatory cells.
• DOSE: by IV infusion at dose of 3 mg/d @ 0, 2, &
6 wks, & then every 8 wks. It can be used along
with MTX to prevent the development of murine
Ab.
• Infliximab neutralizes the biological activity of
TNF.

88. Infliximab
• Serious infections & sepsis has been reported in
some patients treated with both Etanercept &
Infliximab.
• So these agents must not be used in patients
with active infection.
•The efficacy of both Etanercept & Infliximab is
similar with response rates

90. Adlimunab
• It is a human IgG1, antibody to TNF.
• Since it has no foreign protein
components, it is less antigenic than
Infliximab.
• The drug is provided as a premixed syringe
containing 40mg, which is administered
SC injection every 14 days.

91. Adlimunab
•According to randomized control trial
40mg weekly is beneficial.
• It slows the progression of joint damage.
• The common ADR includes URTI, nausea,
flu like symptoms, & rash

92. Anakinara
• It is currently the only available IL-1 ®
antagonist (IL-1RA), which is a naturally
occurring antiinflammatory.
• By binding to IL-1RA on target cells, it
prevents the interaction b/w IL-1 & the
cell.
• IL-1 is playing a key role in the
pathogenesis of RA

93. Anakinara
•The recommended dose is 100mg daily
by self-administered SC.
• Clinical trials evaluating anakinara have
demonstrated significant but modest
improvement in RA signs & symptoms, &
radiology evidence of joint erosion.

94. Surgery
• It plays a role in the management of
patients with severely damaged joints.
• Although arhroplasties & total joint
replacements can be done on a number
of joints.
• The most successful procedures are
carried out on hip, knees, & shoulders.

96. P
R
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G
N
A
N
C
Y

97. Presentation Outlines:
 Introduction
 Epidemiology
Pathogenesis
 Clinical manifestation
 Diagnosis
 Treatment
 Conclusion

98. Conclusion
• RA is a chronic systemic
inflammatory disorder.
• It mainly affects the joints.
• The prevalence of RA is estimated to
be 1% worldwide.
• Both articular and extraarticular
features characterize RA.

99. Conclusion
• To control the pain NSAIDs are used.
• To control the disease DMARDs like
MTX, sulfasalazine, HCQ,
Cyclosporin, cyclophasphamide, AZT,
corticosteroids, & gold can be used.
• These DMARDs are not fully safe, so
monitoring is essential.
• Recently biologic agents are also
used in treatment of RA .

100. • At the end rheumatism licks the
joints but kicks the heart.

101. T
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