Download What is rheumatoid arthritis ?

1987 Revised Criteria for classification of RA
1. Morning stiffness *
2. Arthritis ≥ 3 joints *
3. Arthritis of PIP, MCP or Wrist *
4. Arthritis is Symmetric*
5. Subcutaneous nodules
6. RF
7. Radiographic Changes
Patient must meet ≥ 4 criteria of the above.
N.B: sensitivity 92% and specificity is 89%.
* More
Than 6 Weeks
What is rheumatoid arthritis ?
It ‘s a chronic systemic autoimmune
inflammatory disease affecting all joints
covered by synovium leading to
destructive polyarthritis
RA is the most common inflammatory
arthritis
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causes severe joint destruction
is a systemic disease with systemic damage
leads to disability
Is associated with significant costs
Is an immune mediated disease driven by inflammatory
cytokines
Incidence , prevalence & morbidity
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World wide prevalence: 1-3%
Age distribution:
4F:1M
Peak onset: (35-50)
It can affect any age from childhood up to the age of 75
Life expectancy is reduced by approximately 7 yrs (♂) 3 yrs (♀)
Due to :
Cardiovascular disease
Infection
Renal disease
Respiratory disease
Vasculitis
Malignancy
GI disease
Etio-pathogenesis of RA
No clear aetiology
Multi-factorial
Genetic factors
Auto-Immunity
A- Genetics
• HLA class II is strongly linked to RA.
• HLA DR4 is the major halo-type in ethnic group, HLA DR1 in
Indians and HLA DW15 in Japanese.
N.B :
• 50-70 % of caucasian RA patients are HLA DR4, Compared to 2025 % of the population at large.
• 1st degree relatives of RA patients are 4x
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• 25 % F frequency in identical twins
•5%
Frequency in non-identical twins
B- Auto-Immunity
There is substantial evidence that the initiation of RA is T-cell
mediated.
Antigen Specific Process
Once T-Lymphocyte recognize antigens (Arthritogenic antigen)
Therefore:
Auto Immunity Cascade Started
Arthritogenic Antigen
Endogenous
Bacterial
viral
Exogenous
EBV
Mycoplasma
Hepatitis
MycoBacterium
Paro Virus B19
Yarsenia
Streptococcus
Citrullinated Peptide
Pathogenesis of
Rheumatoid Arthritis (RA)
The Inflammatory Cascade in RA
Activation of T cells triggers a •
series of intercellular
reactions1
Lymphocytes, monocytes/ •
macrophages, and synovial
fibroblasts are stimulated to
release proinflammatory
cytokines2
Cytokines induce synovial •
proliferation and release of
destructive enzymes1-3
B Cell
Macrophage
T Cell
Pannus
IL-1
TNF
Cartilage
Mechanisms of Structural Damage
in Rheumatoid Arthritis1
Osteoclasts
Bone
destruction
TNFa
IL-1
CD4+
T lymphocyte
Joint
erosion
Synoviocytes
Macrophage
Cartilage
destruction
TNFa
IL-1
Chondrocytes
Endothelial cell
Adhesion molecule
expression
Adapted from Arend WP. J Rheumatol Suppl. 2002;65:16-21. Permission to reproduce
granted by Journal of Rheumatology and Dr WP Arend.
Joint-space
narrowing
Cytokine Disequilibrium in the
Disease Process of RA1,2
TNF – A Logical Target
Helps drive events in the inflammatory •
cascade1-3
Triggers production of other cytokines, •
including IL-11,2
TNF
Anti-inflammatory
Proinflammatory
IL-1
IL-6, IL-8, GM-CSF
IL-10, sTNFR,
IL-1Ra
,
Three Destructive Effects of TNF1-5
Activates
monocytes/macrophages
Activates
chondrocytes,
releasing collagenases
Activates osteoclasts,
suppresses osteoblasts
Inflammation
Cartilage
breakdown
Bone resorption
and erosions
The role of B cells in the
pathophysiology of RA
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B cells: key players in RA pathophysiology
• For the past 20 years, RA has been considered a T
cell-mediated disease
• Recently, the important role of B cells in the
pathophysiology of RA has been revealed
• This new discovery has led to a breakthrough in the
management of RA
(Dörner & Burmester, 2003)
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B cells: key players in RA pathophysiology
(cont’d)
• There is an abundance of B cells in the synovium
of
RA-affected joints
– These lymphocytes can be organised into lymphoid
structures
• Three critical roles of B cells in RA pathogenesis:
– Antigen presentation and T cell activation
– Autoantibody production
– Cytokine production
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Role of B cells in RA:
(1) antigen presentation leading to T cell activation
• B cells are highly efficient
antigen-presenting cells
(APCs)
• Antigen presentation
leads to T cell activation
• Activated T cells produce
cytokines that activate
macrophages to produce
pro-inflammatory
cytokines
Results in inflammation and
joint destruction
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Role of B cells in RA: (2) autoantibody production
• Auto reactive B cells
produce auto anti-bodies,
including RF.
• Formation of RF immune
complexes in the
synovium leads to
production of
pro-inflammatory
cytokines through:
– Complement activation
– Macrophage activation
(Abrahams et al, 2000; Silverman & Carson, 2003; Sutton et al, 2000)
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Role of B cells in RA: (3) cytokine production
• Activated B cells produce
cytokines (e.g. TNF-α,
interleukin [IL]-6,
lymphotoxin) which are
known to promote
inflammation and joint
damage in RA
• Lymphotoxin promotes
the formation of new
lymphoid structures in
the synovium, thus
helping to perpetuate
autoimmune reactions
(Duddy et al, 2004; Lund et al, 2005)
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Steps in the maturation of B cells
CD20 only expressed in a subset of B
cells
(Roitt et al, 2002; Sell & Max, 2001; Silverman & Weisman, 2003)
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Pro-inflammatory Cytokines
Stimulate the secretion of:
MMP: degrade matrix and complement protein
MTP “ Acute phase protein”
Prostaglandins “ O2 free radicals”
Heat shock proteins and others!
And these are the major
That mediate tissue destruction
Conclusion of Pathogenesis
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Whatever the initiating stimulus…..
RA is characterized by :
Persistent cellular activation
Genetically susceptible host
Auto-immunity
At the site of articular and extra-articular tissue
chronic inflammation
(PANUS)
and
(JOINT DESTRUCTION(
presentation
• 70% insidious onset (weeks to mnths)
• 10% acute (fulminant onsent)
• 20% sub acute onset
Patterns of joints involvement
• Oligoarticular 45%
• Polyarticular
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35%  60% small joints
30 % large joints
10 % Both
• Monoarticular 20%  50% knee only
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50%  wrist
elbow
shoulder
ankle
hips
1987 Revised Criteria for classification of RA
1. Morning stiffness *
2. Arthritis ≥ 3 joints *
3. Arthritis of PIP, MCP or Wrist *
4. Arthritis is Symmetric*
5. Subcutaneous nodules
6. RF
7. Radiographic Changes
Patient must meet ≥ 4 criteria of the above.
N.B: sensitivity 92% and specificity is 89%.
* More
Than 6 Weeks
Precipitating factors?
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Emotional stress
Infection
Immunization
Pregnancy
Fibromyalgia
Reynaud's phenomenon
Family history (of autoimmune disease )
Extraarticular manifestation of RA
Skin
Pulmonary
Cardiovascular
Hematological
Ocular
CNS
Bone
Amyloidosis
Filty’s Syndrome
Skin
• Palmer erythema
• Reynaud's phenomena
• Rheumatoid nodules up to 25 % of patients
(firm,nontender,single or multiple)
• Vasculaitis 1% PAN like vasculitis
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lekuocytoclastic vasculitis
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cryoglobulonemia
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pulmonary Manifistaions
• Pleurisy (with or without effusion) (frequentoften mild-) 25% bilateral
• Rheumatoid pleural nodules 5% caplan
syndrome (coin shape lesions)
• Diffuse interstitial fibrosis –Rare-• Cricoartynoid involvment
(hoarsness,dysphagia,inspiration dificulty)
Cardiovascular
• Pericarditis 10%, Myocarditis 5%, Valvulitis
(aortic incompitance)<1%
• Coronary artery disease (40% of RA have
prematue atherosclerosis)
• Nodule formation
• Amylodosis
Hematological complications
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Lymph node enlargment 50 %
Anemia of chronic disease
Iron defficency anemia
Autoimmune heamolytic anemia(uncommon)
Drug induced marrow supression anemia
Thrombocytosis
Cytopenia secondary filty’s syndrome
splenomegaly
Ocular
• keratocongunctivitis Sicca (xeropthalmia)
secondary to sjögren’s syndrome
xerostomia,dyspareunia
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Episcleritis benign
Scleritisscleromalcia 1%
Nodules <2% scleromalcia perforance
Uveitis &Congunctivitis are rare
Bone
• Osteoperosis
• AVN(avascular necrosis)
• osteoarthritis
CNS
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Carpal tunnel syndrome (common)
Tarsal tunnel syndrome(rare)
Mono neuritis multiplex
Atlantoaxial subluxation 1/3 of patients
(usually assymptomatic chronic cases)
• CNS Vasculitis
• Depression, Psychosis
• FMS
Secondary amyloidosis
• Renal is the most common
• Skin,liver,GI can be affected
Bad Prognostic Factors
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Early onset
Fulminant course
Seropositive RF
Anti CCP positve
Rheumatoid nodules
Sjogron’s syndrome
Feltty syndrome
Vasculitis
Limtation of biologics
Unlikely to be RA
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Asymmetric Arthritis
Migratory pattern
Predominantly large joints
DIP involvement
Rash, High fever
Back complain
RF Negative status-CCP negative
No erosions in X rays if more than 2 years since
presentation.
Are you a safe physician?
Is the patient with RA fit for the OR?
• Can the Patient get pregnant?
• How to asses activity of the disease by :
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history
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physical exam
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lab
• When to start DMARDS
• When to start Anti TNF
• When to start Anti B-cell
• How to follow up a patient
Managing RA – Therapeutic Goals
• Control symptoms
• Minimize loss of function
• Reduce progression of disease
RA Disease Management
Schematic Representation of the
Course of RA Over 30 Years
Inflammation
Disability
Severity (Arbitrary Units)
Radiographic Scores
0
5
10
15
20
Disease duration (years)
Kirwan J. J Rheumatol. 1999;26:720-5.
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Current RA Treatment Strategy for
2009
DMARD (Step-up/triple therapy)
MTX
SSZ
Biologic 1
Anti-TNF
Biologic 2
Rituximab
Abatacept
DAS28 driven
Etanercept
Infliximab
Adalimumab
ACR Goals of Therapy in RA
Symptom relief
Improvement in physical function
Reduce physical disability
Slowing/arresting progression of structural
damage
Guidelines for the Management of RA. Arthritis Rheum. 1996; 39:713-22.
For early aggressive treatment we
need the following
Early referal
Reliable diagnosis
Prognostic predictors
Effective & safe therapies
Disease activity measures
Decrease disease
activity & prevent
joint damage
Progress in management of RA in recent
years
Drugs
Objectives
1985
MTX/SSZ
Signs &
symptoms
1995
Combination
2000
Concepts
Leflunomide
 joint damage
TNF blockers
Stop joint
damage
Early treatment
Prevent joint
damage
Tight control
Early intensive
ttt
2008
Remission
Traditional Therapies
Exp
methods
MTX,
axathioprine
Penicillamine, gold,
hydroxychloroquine
Physcial medicine,
rehabilitation
Salicylates, NSAIDs
Patient education, rest, application of heat or
cold
Wilske and Haeley. J Rheumatol 1989
Treatment of RA With DMARDs
Traditional DMARDs1
MTX
Hydroxychloroquine
Sulfasalazine
Leflunomide
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•Combination
Treatment2
“Biologics DMARDs”2-5
Etanercept
Infliximab
Adalimumab
Anakinra
Abatacept
Rituximab
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1. ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46:328-346. 2. Combe B, et al. Ann Rheum Dis. 2007;66:34-45. 3.
Kineret® (anakinra) Prescribing Information, Amgen Corporation. Thousand Oaks, Calif. 4. Orencia® (abatacept) Prescribing Information, Bristol-Myers
Squibb Company, Princeton, NJ. 5. Rituxan® (rituximab) Prescribing Information, Genentech, Inc., South San Francisco, Calif.
The Famous Combination Studies
• ARC low dose glucocorticoid study group trial
• Methotrexate-Cyclosporin combination study
• RAIN study of Methotrexate + SSP + HCQ: (triple therapy)
• COBRA study: SSP + MTX + Prednisolone or SSP alone
• Fin-RACo Trial: SSP+MTX+HCQ+Prednisolone vs single
drug +/- Prednisolone
Key Anti-TNF Trials
Late
ARMADA
ATTRACT
TEMPO
Adalimumab
Infliximab
Etanercept
Early
ASPIRE
ERA
PREMIER
Infliximab
Etanercept
Adalimumab
When to use anti-TNF?
Straight away •
Synthesis and Function of TNFa
Soluble TNFa
After DMARD failure •
DAS28 >5.1 or less •
Macrophage or
activated T-cell
Receptor-bound TNFa
Transmembrane
TNFa
Signal Induction
TNFa
Receptor
Late •
Target Cell
Key Messages
Set clear disease activity targets
TICORA
TEAR
CAMERA
Earlier treatment
PROMPT
COMET
Therapeutic memory
BeST
B cell targeting
Definition of Remission
Clinical Remission
– ACR/DAS criteria, or normal acute phase response,
no clinical synovitis
Imaging Remission
– No radiographic damage progression
– No significant synovitis on sensitive imaging
True Remission
– A state of low disease activity with no progression of
structural damage
Clinical Remission by DAS28
DAS28 Score
Disease Activity
Severe
5.1
Moderate
3.2
2.6
Low
Remission DAS28 <2.6
Based on VAS of 100mm
Prevoo MLL et al. Arthritis Rheum 1995;38:44-8. van Gestel AM et al. J Rheumatol 1999;26:705-11.
Remission in RA
Importance of Structural Damage
Determinants of Structural Damage
– Interrelationship synovitis and damage
Remission Clinical and Imaging
– Impact of DMARDs
– Effect of TNF antagonists
Remission on DMARDs
DMARDs frequently produce clinical remission
DMARDs rarely produce imaging remission
Hence DMARDs rarely produce true remission
Explains progression of damage in patients in
clinical remission on DMARDs?
What happens with TNF antagonists?
Algorithm for Achieving Therapeutic
Success in RA
Early RA:
Early DMARD therapy
MTX dose 15-20 mg/week
(within 1-2 months)
+ glucocorticoid
Cobra?
Long-standing RA:
If previosuly inadequate dose:
Optimize DMARD (MTX) dose
+ glucocorticoid
DAS28 improvement >1.2 or
HAQ improvement >0.5
within 3-4 months
YES
NO
SDAI <3.3 or
DAS28 < 2.4 or
HAQ <0.5
within 4 months by adjusting
dosages
X-rays
YES
NO
Switch to another
DMARD
+ glucocorticoid
or
Add a biologic agent
(eg, TNF- antagonist)
Smolen, Sokka, Pincus, Breedveld, Clin Exp Rheumatol 2003
Add another DMARD
+ glucocorticoid
or
Add a biologic agent
(eg,TNF- antagonist)
Continue
DMARD therapy, lower
corticosteroids