Rheumatoid Arthritis by Dr Sarma
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Prof. Dr. Sarma. R.V.S.N M.D.(Med), M.Sc.(Canada), RCGP, FCGP, FIMSA Consultant Physician and Cardio-Metabolic Specialist National Professor of Medicine Visiting Faculty – Frontier Life Line
Visiting Professor of Medicine – SBMC
BioEd Online
Rheumatoid Arthritis (RA): Definition
Progressive, systemic, Autoimmune inflammation
Often aggressive, devastating consequences
Unknown etiology (auto immune, ?infection, smoking)
Characterized by Symmetric synovitis – Chronic Polyarthritis Joint erosions, cartilage and bone destruction Multisystem - extra-articular manifestations Onset usually slow & insidious over months In 15 to 20% may have rapid or acute Aggressive management leads to good control 2
Rheumatoid Arthritis (RA): Epidemiology
Prevalence of - 0.8% to 2.1% of the population
Gender predilection ratio – Women: Men – 3:1
Prevalence increases with age – Juvenile RA
About 40-60% have severe disease – 3 fold mortality
Median life expectancy is shortened by 3 to 7 years
Onset mostly between ages of 35 – 60 years
Genetic – HLA-DR1( 1*0101, 0401) – Class II HCA
Exact etiology is not known 3
Cost of RA versus CAD Costs per patient in $ per year RA
CAD
Direct costs
3790
7929
Indirect costs
2735
1051
Total costs
6525
8980
4
Immunology
5
6
Rheumatoid Arthritis: Pathogenesis Current Treatment Targets
Rheumatoid Factors, anti-CCP
B cell
Immune complexes
Complement
T cell IFN- &
Neutrophil other cytokines
Antigenpresenting cells B cell or macrophage
Synoviocytes
Pannus
Macrophage
Mast cell
TNF
Chondrocytes
IL-1 Osteoclast
Articular cartilage
Production of collagenase and other neutral proteases Bone
7
Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15
Immunology of RA
8
Imbalance in Mediators – Chronic Inflammation
9
The Mediators of Joint Destruction Chemokines IL-1, IL-6 Cytokines
MMP
TNF
VEGF
Immune destruction
10
The Natural Course of RA
Severe RA with Deformities Early RA – Mild Disease Undifferentiated Polyarthritis
11
Time Line of Function Loss in RA
Moderate loss of function
0
2
Severe loss of function
Very severe loss of function
5
10
Years from onset of symptoms 25% require surgical Rx. Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306.
12
Rheumatoid Arthritis: Diagnosis - ACR Criteria
Four or more of the following criteria must be present:
Morning stiffness > 1 hour
Arthritis of > 3 joint areas of the possible 28 joints
Arthritis of hand joints (MCPs, PIPs, wrists)
Symmetric swelling (arthritis) – same joints on both sides
Serum rheumatoid factor – RA Factor (antibody to IgG)
Rheumatoid nodules
Radiographic changes
First
four criteria must be present for 6 weeks or more 13
Rheumatoid Arthritis: Typical Involvement
Wrist joints and MCP joints - very commonly involved
Index and middle Metacarpophalangeal joints
Proximal interphalangeal joints (PIP)
Metacarpophalangeal joints (MCP)
Metatarsophalangeal joints (MTP)
Elbows, Shoulders
Knees, Ankles, Hips. Lumbosacral area is not involved
Spine: only Atlanto-axial joint (C1– C2), subluxation
Terminal interphalangeal (TIPS) joints are not involved
14
The Joints Involved in RA
15
DAS28 (Disease Activity Scoring) for RA - EULAR
Calculated using a formula that includes
Counts for tender and swollen joints – (28 joints)
General health by the patient (on a scale of 0 to 100)
A measurement of ESR or CRP
Score > 5.1 – High disease activity,
Score 5.1 to 3.2 – Moderate disease activity
Score < 3.2 – Low disease activity
Score < 2.6 – Being in Remission
Response to Rx. – of ≥ 1.2 – Good and < 0.6 – Poor European League Against Rheumatism (EULAR) 16
Rheumatoid Arthritis – ACR Functional Classes Classification Specifications of activity levels
Class I
Complete ability to perform daily activities self-care, vocational and avocational
Class II
Ability to perform usual self-care and vocational activities; limited avocational activities
Class III
Ability to perform usual self-care activities; limited vocational or avocational activities
Class IV
Limited ability to perform usual self-care or vocational or avocational activities 17
Extra Articular Manifestations of RA Systemic involvement
Special Features
Musculoskeletal wasting
Episcleritis, Scleromalacia
Tenosynovitis, Bursitis
Pleural effusion, Nodules
Osteoporosis, Rh nodules
Cervical cord compression
Vasculitis, Arteritis
Mononeutitis, carpel tunnel
Pericarditis, Myocarditis
Felty’s syndrome, Caplan’s
18
19
20
Swan-Neck and Boutonniere Deformities in RA
http://images.rheumatology.org – Album of American College of Rheumatology 21
22
23
Radiological Changes in Rheumatoid Arthritis
24
Erosion of the Odontoid process
Atlanto-Axial subluxation 25
Blood Parameters in RA
Acute Phase Reactants (APR ) C-Reactive Protein (CRP) - > 4 mg% -
It is the single most useful marker ESR is raised > 30 mm – other confounders Ceruloplasmin
Haptoglobin (Hp)
Leukocytosis, Nutrophilia
Normocytic normochromic anemia
Thrombocytosis 26
Synovial Fluid in RA
No need in general for joint aspiration
Required to exclude other causes of arthritis
Inflammatory arthritis picture Turbid fluid with reduced viscosity Increased protein content
Decreased glucose content
WBC count from 2,000 to 50,000/l PMNLs predominate
Total compliment, C3 and C4 are markedly
27
Rheumatoid Factor (RA Factor)
Developed by Eric Waller in 1937 – Rose Waller Test
Agglutinating Abs - Latex particle agglutination assay
Isotype specific enzyme immunoassays – New technique
Antibodies to Fc portion of our own IgG - These Abs are IgM
Positive in 5% of normal persons and in only 70-80% of RA
Low specificity (false +ves) & low sensitivity (false –ves.)
It is not a screening or Dx. tool – More a prognostic tool
It is negative in 30% cases of RA – Sero negative RA
RF are commonly seen other disease – see next slide 28
Positive Rheumatoid Factor is seen in: Disease
Frequency
Advanced Rheumatoid Arthritis
100%
Rheumatoid Arthritis (over all)
70%
Sjögren's syndrome
90%
Systemic Lupus Erythematosis (SLE)
30%
Sub acute bacterial endocarditis (SABE)
40%
Tuberculosis
15%
Old Age
20%
Normal healthy individuals
5% 29
Anti-CCP Antibody Test in RA (ACPA)
Antibodies to Cyclic Citrullinated Peptides (anti-CCP)
Similar sensitivity for RA (70%)
Specificity for RA (>95%) better than RA Factor
In early polyarthritis anti-CCP are useful for Dx.
Anti-CCP are associated with more severe disease
They spell a poor prognosis and rapid progression
They may be positive in asymptomatic patients years before the onset of symptoms
30
Serology in Rheumatoid Arthritis Test
RA Factor is IgM Antibody to the Fc portion of the IgG Anti CCP: Antibodies to Cyclic Citrullinated Peptides 31
Differential Diagnosis of RA
Connective tissue diseases - Scleroderma and SLE
Fibromyalgia, Palindromic Rheumatism
Infectious endocarditis, Acute Rheumatic Fever
Poly articular gout
Polymyalgia Rheumatica
Sarcoidosis, Hemochromatosis
Sero negative spondylo arthropathies
Reactive arthritis - evaluate for psoriasis, Reiter’s, IBD
Still’s disease, Thyroid disease, Viral arthritis 32
Rheumatoid Arthritis v/s Osteoarthritis Feature
Rheumatoid Arthritis
Osteoarthritis
Pathology
Autoimmune
Degenerative
Age
Any age – usually 35+
Increases with age
Joints involved
Small joints MCP, PIP
Large joints, TIP
Spine (Axial)
C1-C2 - Subluxation
Lumbosacral
Extra articular
Many systemic effects
Few systemic effects
Course
Rapidly progressive
Slowly progressive
Disability
Highly disabling
Mild to moderate 33
Early Progression of Bone Erosions in RA
34
Rheumatoid Arthritis: Predictors of Prognosis
Presence of > 20 inflamed joints
Markedly elevated ESR
Radiographic evidence of bone erosions
40%-85% of RA pts unable to work in 8Presence of rheumatoid nodules High titers of RA Factor10 andyears anti CCP
Higher class of functional disability
Persistent inflammation; comorbidities
Advanced age of onset
Low socio-economic status, low education level
HLA-DR*0401 or DR*0404 35
Rheumatoid Arthritis: Complications
Carpal tunnel syndrome,
Baker’s cyst, Subcutaneous nodules,
Systemic Vasculitis,
Sjögren’s syndrome,
Peripheral neuropathy,
Cardiac and pulmonary involvement,
Felty’s syndrome, and anemia
Risk of lymphomas three times greater
Risk of infection due to disease and treatment 36
Goals of Therapy 1.
Relief of pain
2.
Reduction of inflammation
3.
Protection of articular structures
4.
Maintenance of functional activity
5.
Control of systemic involvement
6.
Slow the progression of disease
7.
Increase the over all quality of life
37
Non Pharmacological Management
Rest
Exercise
Flexibility/stretching
Muscle conditioning
Cardiovascular/aerobic
Diet
Weight management
Physical and occupational therapy
38
Therapeutic Window of Opportunity
Erosive changes occur early in disease
Even a brief delay of therapy can have a significant impact on disease parameters years later
Early DMARD treatment to arrest progression
MTX is the sheet anchor – Combination of DMARDs
Bridge the gap initially with NSAID and GC
Biologics only for refractory case – with caution; cost
Surgical treatment options in selected patients O’Dell JR. Arthritis Rheum. 2002;46:283-285. Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.
Therapeutic Window of Opportunity
Erosive changes occur early in disease
Even a brief delay of therapy can have a significant impact on disease parameters years later
Surgical Treatment will be mandated in Early DMARD treatment to arrest progression 25%
MTX is the sheet anchor – Combination of DMARDs
Bridge the gap initially with NSAID and GC
Biologics only for refractory case – with caution; cost
Surgical treatment options in selected patients O’Dell JR. Arthritis Rheum. 2002;46:283-285. Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.
Medical Management – Drug Classes Classes
NSAIDs – Cox-1 & Cox-2 inhibitors Glucocorticoids – Prednisolone, MP IAS – Intra articular steroids DMARDs – MTX, SSZ, HCQ, CQ Immunosuppressive Rx.– AZT, Leflunomide, CS Cytotoxic agents – Cyclophosphamide Biologics – TNF-
antibodies, IL-1 R antagonist
Old drugs – Gold salts, D-Penicillamine 41
NSAIDS in RA
NSAIDs COX 1 Constituent pathway Renal and GI homeostasis
COX2 Inducible pathway Inflammation
Selective COX 2 Inhibitors
Improved GI tolerability
Reduced effects on RBF
No effect on platelets
Called as COXIBs
May have adverse effect on heart
Celecoxib
Etoricoxib
Meloxicam
42
NSAID Class of Drugs Non Selective
NSAIDs used as analgesics
Ibuprofen
Ketorolac
Ketoprofen
Aspirin (NSAID)
Diclofenac
Selective COX-2
Aceclofenac
Celecoxib, Etoricoxib
Piroxicam
Meloxicam
Lornaxicam
Analgesics
Naproxen
Tramadol
Indomethacin
Paracetamol 43
Pros and Cons of NSAID Therapy PROS
Effective control of inflammation and pain Effective reduction in swelling
CONS
Improves mobility, flexibility, range of motion
Improve quality of life
Relatively low-cost
Does not affect disease progression GI toxicity common Renal complications (eg. Irreversible renal insufficiency, papillary necrosis)
Hepatic dysfunction
CNS toxicity
44
Pros and Cons of Corticosteroid Therapy PROS
Anti-inflammatory and immunosuppressive effects Can be used to bridge gap between initiation of DMARD therapy and onset of action Intra-articular steroid (IAS) injections can be used for individual joint flares
CONS
Does not conclusively affect disease progression Tapering and discontinuation of use often unsuccessful Low doses result in skin thinning, ecchymoses, and Cushingoid appearance
Significant cause of steroidinduced osteopenia 45
Methotrexate (MTX)
MTX is given 10 to 30 mg orally, IM, or SC per week It is DHF reductase inhibitor – Supplemental folic acid The clinical improvement takes one to two months Nausea, diarrhea; mouth ulcers; rash, alopecia; Abnormal LFT Rare: low WBC & platelets; pneumonitis; sepsis; liver disease; EBV related lymphoma; CBC, creatinine, and LFTs monthly for six months, then every one to two months; repeat AST or ALT in two to four weeks if initially elevated, and adjust dose as needed; Rapid onset (six to 10 weeks); tends to produce more sustained results over time than other DMARDs and lowers all-cause mortality; Can be used when cause of polyarthritis uncertain; Often combined with other DMARDs like Leflunomide, SSZ, HCQ 46
Changing Paradigm of Treatment
Evolving paradigm
Current Treatment Traditional DMARDs
• Early
Aggressive Rx. • Biological • Combination treatment
47
48
49
New Treatment Paradigm for RA
Orthopedic surgery
Occupational therapy
Higher dose steroids for flares or extraarticular disease
Intraarticular steroids
Physical therapy
Patient education
Simple analgesic
Weaver AL, 2008.
50
Biological Agents in RA
TNFα antagonists
Adalimumab (Humira)
Etanercept (Enbrel)
Infliximab (Remicade)
Interleukin-1 antagonist
Suppressors of T-Cell activation
Anakinra (Kineret) Abatacept (Orencia)
Anti B-Cell monoclonal antibody
Rituximab (Rituxan) 51
Characteristics of Biologicals used in RA Etanercept Enbrel
Infliximab Remicade
Adalimumab Humira
Anakinra Kineret
Abatacept Orencia
Rituximab Rituxan
Target
TNF
TNF
TNF
IL-1 Receptor
T-Cell Activation
B-Cell
Half Life
3-5 Days
8-10 Days
10-20 Days
4-6 Hrs
13-16 Days
19 Days
Construct
Human
Chimeric
Human
Human
Human
Chimeric
Dosing
Once Biweeklyweekly
Once every 4-8 weeks
Once every 1-2 weeks
Once Daily
Once Monthly
Twice every 6-12 months
Route
Sub-Cut
I.V.
Sub-Cut
Sub-Cut
I.V.
I.V.
52
Biologics: Relative Contraindications
Active Hepatitis B Infection
Multiple sclerosis, optic neuritis
Active serious infections
Chronic or recurrent infections
Current neoplasia
History of TB or evidence of Koch’s
Congestive heart failure (Class III or IV)
53
Safety Considerations of Biologicals
Serious Infections
Opportunistic infections (TB)
Malignancies/lymphoma
Demyelination
Hematologic abnormalities
Administration reactions
Congestive heart failure
Hepatic
Autoantibodies and drug induced lupus Vaccination
54
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