prof. dr. sarma. r.v.s.n m.d.(med), m.sc.(canada), rcgp, fcgp, fimsa consultant physician and
DESCRIPTION
Website: www.drsarma.in. You Tube: drsarmaji channel. Rheumatoid Arthritis. 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 - PowerPoint PPT PresentationTRANSCRIPT
BioEd Online
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
Website: www.drsarma.inWebsite: www.drsarma.inYou Tube: drsarmaji channelYou Tube: drsarmaji channel
22
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
33
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
44
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
Immunology
55
66
Rheumatoid Arthritis: Pathogenesis
77Adapted from Arend WP, Dayer JM. Arthritis Rheum.
1990;33:305–15
B cell
T cell
Antigen-presenting
cells
B cell ormacrophage Synoviocytes
Pannus
Articular cartilage
Chondrocytes
Macrophage
HLA-DRother cytokines
IFN- &
Production of collagenase and other
neutral proteases
Osteoclast
TNF
IL-1
Rheumatoid
Factors, anti-CCP
Immune complexes
Bone
Complement
Neutrophil
Mast cell
Current Treatment Targets
Immunology of RA
88
Imbalance in Mediators – Chronic Inflammation
99
The Mediators of Joint Destruction
1010
The Natural Course of RA
1111
Time Line of Function Loss in RA
1212Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306.
Moderate loss of function
Severe loss of function
Very severe loss of
function
0 1052
Years from onset of symptoms
Years from onset of symptoms
25% require surgical Rx.25% require surgical Rx.
Rheumatoid Arthritis: Diagnosis - ACR Criteria
1313
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
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
1414
The Joints Involved in RA
1515
1616
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)
Rheumatoid Arthritis – ACR Functional Classes
Classification
Specifications of activity levels
Class IComplete ability to perform daily activitiesself-care, vocational and avocational
Class IIAbility 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 IVLimited ability to perform usual self-care or vocational or avocational activities
1717
Extra Articular Manifestations of RA
1818
1919
2020
Swan-Neck and Boutonniere Deformities in RA
2121
http://images.rheumatology.org – Album of American College of Rheumatology
2222
2323
Radiological Changes in Rheumatoid Arthritis
2424
2525
Erosion of the Odontoid processErosion of the Odontoid process
Atlanto-Axial subluxationAtlanto-Axial subluxation
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
2626
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
2727
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
2828
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%
2929
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
3030
Serology in Rheumatoid Arthritis
3131
Test
RA Factor is IgM Antibody to the Fc portion of the IgG
Anti CCP: Antibodies to Cyclic Citrullinated Peptides
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 arthritis3232
Rheumatoid Arthritis v/s Osteoarthritis
3333
FeatureRheumatoid Arthritis
Osteoarthritis
Pathology Autoimmune Degenerative
AgeAny 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
CourseRapidly progressive
Slowly progressive
Disability Highly disabling Mild to moderate
Early Progression of Bone Erosions in RA
3434
Rheumatoid Arthritis: Predictors of Prognosis Presence of > 20 inflamed joints
Markedly elevated ESR
Radiographic evidence of bone erosions
Presence of rheumatoid nodules
High titers of RA Factor and 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
3535
40%-85% of RA pts unable to work in 8-10 years
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
3636
Rheumatoid Arthritis: Complications
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
3737
Non Pharmacological Management
Rest Exercise
Flexibility/stretching Muscle conditioning Cardiovascular/aerobic
Diet Weight management Physical and occupational therapy
3838
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
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.
Surgical Treatment will be mandated in 25%
Medical Management – Drug Classes
4141
NSAIDS in RA
4242
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
Constituent pathway
Renal and GI homeostasis
Inducible pathway
Inflammation
NSAID Class of Drugs
Non Selective
Ibuprofen
Ketoprofen
Diclofenac
Aceclofenac
Piroxicam
Lornaxicam
Naproxen
Indomethacin
NSAIDs used as analgesics
Ketorolac
Aspirin (NSAID)
Selective COX-2
Celecoxib, Etoricoxib
Meloxicam
Analgesics
Tramadol
Paracetamol4343
Pros and Cons of NSAID Therapy
PROS
Effective control of inflammation and pain
Effective reduction in swelling
Improves mobility, flexibility, range of motion
Improve quality of life
Relatively low-cost
CONS
Does not affect disease progression
GI toxicity common
Renal complications (eg. Irreversible renal insufficiency, papillary necrosis)
Hepatic dysfunction
CNS toxicity
4444
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 steroid-induced osteopenia
4545
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,
HCQ4646
Changing Paradigm of Treatment
4747
Current TreatmentTraditional DMARDs
4848
4949
New Treatment Paradigm for RA
5050
Orthopedic surgeryHigher dose steroids for flares or extraarticular disease
Occupational therapy
Physical therapy
Patienteducation
Intraarticular steroids
Simple analgesic
Weaver AL, 2008.
Biological Agents in RA
TNFα antagonists Adalimumab (Humira) Etanercept (Enbrel) Infliximab (Remicade)
Interleukin-1 antagonist Anakinra (Kineret)
Suppressors of T-Cell activation Abatacept (Orencia)
Anti B-Cell monoclonal antibody Rituximab (Rituxan)
5151
Characteristics of Biologicals used in RA
5252
Etanercept
Enbrel
Infliximab
Remicade
Adalimumab
Humira
Anakinra
Kineret
Abatacept
Orencia
Rituximab
Rituxan
Target TNF TNF TNFIL-1
ReceptorT-Cell
ActivationB-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
DosingOnce
Biweekly-weekly
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.
Biologics: Relative Contraindications
5353
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)
Safety Considerations of Biologicals
5454
Serious Infections
Opportunistic infections (TB)
Malignancies/lymphoma
Demyelination
Hematologic abnormalities
Administration reactions
Congestive heart failure
Hepatic
Autoantibodies and drug induced lupus
Vaccination
BioEd Online
www.drsarma.inwww.drsarma.in