Rheumatology

1. Rheumatoid Arthritis
By Dr. Bharath Raj K
1

2. Definition
• Chronic inflammatory disorder of unknown
aetiology characterized by Symmetric
Polyarthritis (MC form of Chronic inflammatory
arthritis)
2

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
3

4. Genetics
• 1st Degree Relative
• HLA DRB1 gene  MHC 2 β chain  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
4

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
5

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  IFNγ and 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 6

7. 7

8. PATHOLOGY
• Synovial inflammation & proliferation
• Focal bone erosions
• Thinning of articular cartilage
• PANNUS formation
• Resorption lacunae in interface of synovial
membrane with periosteal surface
• Periarticular osteopenia
• Thinning of bony trabeculae
• Cortical bone thinning
• Generalised osteoporosis(marrow cavity involved)
8

9. 9

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
10

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( 1st MCP subluxation +
Hyperextension of 1st 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
12

13. 13

14. 14

15. 15

16. 16

17. 17

18. 18

19. 19

20. 20

21. 21

22. 22

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
23

24. 24

25. 25

26. 26

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
27

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
28

29. 29

30. 30

31. 31

32. Measurement of Disease Progression
• To determine the progression of RA, patients are categorized by clinical and
radiologic criteria 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
destruction in 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 32

33. TREATMENT
33
• 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
34

35. NSAIDs
• Adjunctive agents in Rx of RA
• Non selective COX1 &COX 2 Inhibition
S/E:
• Chronic Gastritis
• Peptic ulcer disease
• CRF
35

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
36

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

38. 38

39. 39

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 40

41. 41

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 42

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
43

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
44

45. 45

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
46

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
47

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
48

49. 49

50. 50

51. 51

52. 52

53. 53