Rheumatoid Arthritis Pathology, C/F and Diagnosis and Mx.ppt

Rheumatology

1. Rheumatoid Arthritis
By Dr. Bharath Raj K
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2. Definition
•Chronic inflammatory disorder of unknown
aetiology characterized by Symmetric
Polyarthritis (MC form of Chronic inflammatory
arthritis)
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3. Epidemiology
•0.5-1% of Adult pop
•Asia & Africa –Low prevalence = 0.2-0.4%
•F > M = 2-3:1
•Estrogen TNF αEnhance immune response
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4. Genetics
•1
st
Degree Relative
•HLA DRB1 gene MHC 2 βchain Shared Epitope(SE)
•Carriers of SE allele Anti-CCP Ab production worse
outcome
•High Risk Alleles = 0401
•Moderate Risk Alleles = 0101 4040 0901 1001
•GWAS position of 11,71,74 of HLA-DRB1 ; 9 of HLA-B
; 9 of HLA-DPB1
•PTNP22 geneAnti-CCP positive diseaseEurope
•PADI4 geneAsian pop.
•APOM East Asian pop.inc. risk of Dyslipidemia too
•Micro RNA miR146a/miR155
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5. Environmental factors
•Cigarette smoking-> Anti-CCP AB positive cases
•EBV
•Peridontitis Porphyromonas gingivialis 
PAD( peptidy arginine deiminase) enzyme
Cirtullination of arginine Ab against citrulline
Anti-CCP Ab
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6. PATHOGENESIS
•GENETICS + ENVIRONMENT FACTORS
•Modification of our own Ag
•Citrullination in Type 2 collagen and Vimentin
•APC detecting citrullinated cells as Foreign Ag
•Cd4+ T cells B cellsPlasma cells Ig production
•T cells IFNγand IL 17 MacrophagesTNFα,
IL 1 , IL6Synovial cell proliferation & PANNUS
•Inflammatory cytokines T cellsRANK L 
OsteoclastsResorption lacunae of bone
•Ab RF & Anti-CCP Immune complexes 
Complement activation Inflammation
•Chronic Inflammation Angiogenesis
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8. PATHOLOGY
•Synovial inflammation & proliferation
•Focal bone erosions
•Thinning of articular cartilage
•PANNUSformation
•Resorption lacunae in interface of synovial
membrane with periosteal surface
•Periarticular osteopenia
•Thinning of bony trabeculae
•Cortical bone thinning
•Generalised osteoporosis(marrow cavity involved)
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10. CLINICAL FEATURES
•Incidence 25 to 55 yrs
•Early Morning stiffness > 1 hour eases with physical
activity
•Initial joints involved = Small joints of hands & feet
Wrist , MCP, PIP = RA
DIP = OA coexistent
•Initial pattern = Mono, Oligo / Polyarthritis , Symmetric
•Undifferentiated Inflammatory arthritis = too few joints
involved
•FLEXOR TENDON TENOYNOVITIS = Freq.
Hallmark of RA
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11. Deformities:
•Ulnar deviation(MCP subluxation)
•Swan neck deformity(Hyperextension of PIP &
Flexion of DIP)
•Boutonniere deformity(Flexion of PIP &
Hyperextension of DIP)
•Z line deformity( 1
st
MCP subluxation +
Hyperextension of 1
st
IP)
•Piano key movement of ulnar styloid
•Pes planovalgus= FLAT FEET
•Atlantoaxial Cx spine involvement 
Compressive myelopathy 11

12. Constitutional C/F
•Fever
•Weight loss
•Malaise
•Depression
•Cachexia
•Fever>38.3’C Systemic Vasculitis/Infection
ASSOCIATED CONDNS.:
•CVS MCC of death in RA Carotid atherosclerosis
& CAD
•Osteoporosis
•Hypoandrogenism
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23. Diagnosis
•ACR & EULAR criteria 2010
•More specific since Antibodies tested
•Classification criteria
•No need of Radiographic joint damage /
rheumatoid nodules for classification criteria
•Presence of radiographic joint erosions/SC
nodules later stages of disease
•Criteria = Joint involved + Serology + APR +
Duration of C/F
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27. Lab diagnosis
Serology test:
•ESR
•CRP
•IgM RF –sensitivity = 75-80%
•AntiCCP Ab = Specific -95%
•Synovial fluid analysis –5000-50000 WBC/μl,
Neutrophil predominance
D/D: Gout , Pseudogout , Infection , OA
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28. IMAGING
X-Ray :
•Periarticular osteopenia
•Soft tissue swelling, Symmetric joint space loss,
Subchondral erosions in wrists and hands and feet
•Deformities
MRI :
•Detect Synovitis & joint effusions
•Detect Early bone and bone marrow changes
•BM oedema Early sign of inflammatory joint d/o
•USG colour doppler:
•Increased joint vascularityinflammation
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32. Measurement of Disease Progression
•To determine the progression of RA, patients are categorized by clinicaland
radiologiccriteria into 4 stages, as follows:
•Stage I (early RA) –No destructive changes observed upon radiographic
examination; radiographic evidence of osteoporosis is possible
•Stage II (moderate progression) –Radiographic evidence of periarticular
osteoporosis, with or without slight subchondral bone destruction; slight cartilage
destruction is possible; joint mobility is possibly limited, but no joint deformities
are observed; adjacent muscle atrophy is present; extra-articular soft tissue lesions
(e.g., nodules and tenosynovitis) are possible
•Stage III (severe progression) –Radiographic evidence of cartilage and bone
destructionin addition to periarticular osteoporosis; joint deformity (e.g.,
subluxation, ulnar deviation, or hyperextension) without fibrous or bony
ankylosis; muscle atrophy is extensive; extra-articular soft tissue lesions (e.g.,
nodules, tenosynovitis) are possible
•Stage IV (terminal progression) –Presence of fibrous or bony ankylosis, along
with criteria of stage III
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33. TREATMENT
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•ACR 20,50,70 Improvement Criteria = Clinical trials
•DAS 28 -Disease Activity Score 28 joint
•SDAI -Simplified Disease Activity Index
•CDAI -Clinical Disease Activity Index
•RAPID3 –Routine Assessment of Patient Index Data 3
•PAS
•PAS Ⅱ
•Continuous measures of disease activity

34. Rx Options
•NSAIDs
•Glucocorticoids
•Conventional DMARDs
•Biologic DMARDs
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35. NSAIDs
•Adjunctive agents in Rx of RA
•Non selective COX1 &COX 2 Inhibition
S/E:
•Chronic Gastritis
•Peptic ulcer disease
•CRF
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36. DMARDs
•Conventional= Mtx, HCQs, Sulfasalazine, Leflunomide
•Not in Use= Minocycline, Gold salts, Penicillamine,
Azathioprine, Cyclosporine
•Delayed onset of action = 6-12 weeks
•Slow/prevent Structural progression of RA
•Mtx= Methotrexate= Benchmark of efficacy
•HCQs = not TRUE DMARD = doesn’t delay
radiographic progression
used in early & mild disease / Adjunctive Rx in combo
with other DMARDs
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37. Glucocorticoids
1.Low to Moderate dosesRapid disease control 
before onset of fully effective DMARD therapy
2.1-2 week burst of GlucocorticoidsAcute flare
3.Low dose Prednisone = 5-10mg/d Inadequate
response to DMARDs
4.High doses Steroids > 10mg/day Prednisone Severe
Extra Articular C/F ILD
5.One/Few Joints IntraArticular Inj. Triamcinolone
acetonide Exclude Infection Mimic Flare
S/E:
•Osteoporosis Bisphosphonate –Primary Prevention
•PUD 37

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40. Biologics
Anti -TNF agents:
•Infliximab= Chimeric Monoclonal Ab
•Adalimumab& Golimumab= Humanized monoclonal Ab
•Etanercept= TNF Receptor 2 binding to Fc portion of IgG1
•Certolizumab= Pegylated Fc free fragment binding to TNFα
Can be used as Monotherapy
S/E:
•Serious Bact. Inf.
•Oppurtunistic fungal inf.
•Reactivation of Latent TB
C/I:
•Chronic Hep B
•Class 3/4 Heart Failure
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42. NON TNF agents:
ANAKINRA:
•IL1 R antagonist
•Limited now in RA Rx
•New Indications: Neonatal-onset Inflammatory d/o,
Muckle-Wells syndrome, Familial Cold Urticaria,
Systemic JIA , Adult onset Still disease
•Not combined with Anti-TNF agents –serious infection
ABATCEPT:
•inhibit CD28-CD80/86 interactions & inhibit APC
function by reverse signaling Thro CD80 & 86
•Combo with Mtx / other DMARD
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43. RITUXIMAB:
•Chimeric Monoclonal Ab Anti CD20
•Refractory RA in combo with Mtx
•Seropositive > Seronegative cases
S/E:
•Mild to moderate Infusion reaction
•Hep B reactivation
•PML
•Lethal brain d/o(rare)
TOCILIZUMAB:
•Humanized monoclonal AbIL-6
•Monotherapy / Combo with Mtx/ other DMARDs
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44. Small Molecule agents
TOFACITINIB:
•JAK1 & JAK3 inhibition
•Oral Rx = efficacy of Biologics
•Monotherapy/ Combo with Mtx
S/E:
•Inc. Transaminases
•Neutropenia
•Inc. Cholesterol levels
•Inc. serum creatinine
•Inc. Risk of Infection
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46. Treatment of EA C/F
•RA-ILD
•Rx with High Dose Steroids +
Immunosuppressants= Azathioprine,
Mycophenolate mofetil, Rituximab
•Aggressive Mx of early diseasePrevent
Occurrence
•Other C/F Underlying RA Rx covers
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47. ACR 2015 Rx Guidelines
•Early (<6 months of disease duration)
•Established(>6months)
Physical therapy :
•Dynamic strength training
•Physical activity = 30 min of moderately intensity activity most
days a week
•Foot Orthotic = Painful valgus deformity
•Wrist Splints
Surgery:
•Knee, Hip, Shoulder, Elbow = Total joint arthroplasty
•Silicone implants MCP arthroplasty
•Arthrodesis & Total wrist Arthroplasty
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48. Pregnancy:
•75% = Improvement of symptoms
•Flare Glucocorticoids Low dose
•HCQs & Sulfasalazine = Safest DMARDs
•Mtx & Leflunomide Category X
•Biologics = Avoided
•Elderly:
•> 60 yrs
•Less aggressive Rx with less drug toxicity
•NSAIDs= decline in renal function
•Mtx= Avoided in S.Cr > 2mg/dl
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