Rheumatoid Arthritis by Dr Sarma

January 29, 2018 | Author: Anonymous | Category: Science, Health Science, Immunology
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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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