2. • Rheumatology is a strongly clinical discipline that
mainly depends on pattern recognition .
3. • Primary symptoms:
• Pain
• Joint stiffness
• Swelling
• Limitation of motion
• Weakness
• Fatigue
• Loss of function
4. • Initial rheumatic history and physical examination to determine
1.is it articular?
2.is it acute or chronic ?
3.is inflammation is present ?
4.how many /which joint are involved ?
• Key question to approach the disease.
5. • Other important questions we have to assess
1. symmetrical joint involvement ?
2. duration of prolonged morning stiffness?
3. pain relation with activity /inactivity ?
4.constitutional symptoms ?
5. any rash/skin lesions are present ?
6. Articular or non-articular??
Articular Non-articular
Deep or diffuse pain Point or focal tenderness in regions adjacent to
articular structures
Pain or limited range of motion on active and passive
movement
Painful on active, but not passive range of motion
Physical findings in the joint Physical findings remote from the joint capsule
Demonstrate swelling, crepitus, instability and
deformity of the joint
Seldom demonstrate swelling, crepitus, instability or
deformity of the joint
7. • Duration :
acute < 6 weeks
chronic > 6 weeks
• Number of joints :
one joint – mono articular
> one joint - poly articular
( 2 or 3 joints –oligo/pauci articular , 4 or more – poly articular )
8. • JOINT COUNT : 28 joint should be examined
PIP
MCP
WRIST JOINT
ELBOW JOINT
SHOULDER JOINT
KNEE JOINT
• Das 28 score
9. • Inflammation of joints :
1. acute inflammation : clinical features
‘red ,hot ,tender ,swollen ,loss of function “
true in acute inflammatory arthritis
10. 2. chronic inflammation :
mainly by -clinical history ( 60 to 80 % diagnostic information )
- 15 to 30 % physical exam
- 5 to 15% investigations
inactivity worsens the symptoms ( Early morning stiffness)
activity improves the symptoms (gentle exercises )
16. Patterns of inflammatory arthritis :
1. only peripheral arthritis :
both upper and lower segment of body affected
a. symmetrical : RA , mimics of RA
b. asymmetrical : SpA , occasional peripheral SpA
2. primarily below waist asymmetrical large joint arthritis :
peripheral SpA
3. mainly spinal diseases with or without peripheral arthritis :
axial SpA
25. Migratory polyarthritis:
Typical (classical) pattern ; arthritis
does not remain in a single joint more
than 7 days .
Rheumatic fever
Migratory element Gonococcal arthritis
Viral arthritis
SLE
Idiopathic juvenile arthritis
Poly articular gout
Acute reactive arthritis
others
33. • Laboratory tests need to be interpreted in the proper clinical context
keeping in mind pre-test probability of the disease and work in a
“probabilistic” process of diagnosis.
34. ESR
• Recommended technique- Westergren technique by International Committee for
Standardization in Hematology
• Upper limits of Normal- 15 mm/hr for males and 20 mm/hr for females
• Upper limit of normal ESR:
In men: Age in years/2
In women: 10 plus age in years/2
36. • ESR is influenced by several factors
• Plasma proteins like fibrinogen- Pregnancy, diabetes, end stage renal disease,
heart disease have elevated ESR
• RBC factors- microcytosis, polycythemia and abnormally shaped RBCs lower
ESR
• Elevated in Obesity
37. C-Reactive protein
• Identified first in 1930 as a protein that could bind C polysaccharide of
streptococcus pneumoniae cell wall
• After acute inflammatory stimulus ,concentrations increase rapidly and peak at 2
to 3 days at levels that reflect extent of tissue injury
• Most healthy adults have levels less than 0.3 mg/dl
• Techniques available- immunoassays and laser nephelometry
38. • Marked Elevation of CRP ( >10mg/dl)
• Acute bacterial infection
• Major trauma
• Systemic vasculitis
40. • Normal or minor elevation ( <1mg/dl)
• Vigorous exercise
• Common cold
• Pregnancy
• Gingivitis
• Seizures
• Depression
• Insulin resistance and diabetes
• Obesity
41.
42. ESR vs CRP
ESR CRP
Advantages Much clinical information in
literature
May reflect overall health status
Rapid response to inflammatory
stimuli
Wide range of clinically relevant
values
Unaffected by age and gender
Reflects value of a single acute
phase protein
Can be measured on stored sera
Quantitation is precise and
reproducible
43. ESR vs CRP
ESR CRP
Disadvantages Affected by RBC morphology
Affected by Anemia and
polycythemia
Reflects levels of any proteins,
none of which are Acute phase
Responds slowly to inflammation
Requires fresh sample
May be affected by drugs
Not sensitive to changes in SLE
disease activity
44. Rheumatoid factor:
• Autoantibodies that recognize Fc portion of IgG
• Earliest assays ( Rose- Waaler agglutination test) were developed in 1940s
• May be positive in up to 1% of normal young adults and up to 5% of those more
than 70 years of age
• Sensitivity and specificity range from 50%-90%
• PRETEST PROBABILITY OF RA IS VERY IMPORTANT IN INTERPRETING RF
POSITIVITY.
45. • Methodologies
• Radio-immunoassays
• ELISA
• Nephelometry
• Reference range – less than 15 IU/mL or less than 1:16
• High titres indicate severe disease
47. Other causes of RF positivity
• Normal individuals
• SLE
• Polymyositis
• Tuberculosis
• Syphilis
• Viral hepatitis
• Infectious mononucleosis
• Influenza
48. Anti-cyclic citrullinated peptide antibodies
• Citrulllinated Proteins are now considered to be at the core of pathogenesis in RA
• Most assays use Filaggerin as the antigen
• Anti CCP 3rd generation assays have sensitivity of 82.9% and specificity of 93-
94%
• CCP is basically a lab construct to detect Anti citrullinated Protein antibodies
49. Anti-cyclic citrullinated protein antibodies…
• Aim to detect antibodies against a multiplicity of citrullinated proteins considered
to be targets involved in pathogenesis of RA
• ACPAs are slightly more sensitive as compared to Anti- CCPs being positive in
approx 10% of Anti- CCP negative patients.
• May be detected in preclinical RA
50. Clinical relevance of anti-CCP/CPA
• High specificity for RA
• Predictor for development of RA
• More than 90% patients of undifferentiated arthritis with Anti-CCP positive
develop RA within 3 years
• Predict more severe and disease course
• Associated with RA- related ILD and cardiovascular disease
52. • Combined testing for RF and Anti- CCP is the current standard-
specificity reaches 100% however sensitivity may be lowered
53. Anti-Nuclear Antibodies
• Wide diversity of autoantibodies directed against multiple intra-cellular antigens
consisting of nuclear specificities such as DNA or small nuclear RNPs
• First described in 1948
• Evolved from clinical pathologic observations to be tools in the study of cellular
biochemical processes
54.
55. Which method to use?
• Immunofluorescence is the Gold standard
• ELISA has lower accuracy
56. • Pattern of ANA reflects the intracellular target of ANA- may help in
deciding most appropriate antibody by second line
tests(Immunoblot)
Pattern Antibody to Disease
Homogenous DNA, histone SLE,DLE
Speckled RNP, Sm,
SSA/Ro, SSB/La
SLE
SLE,SS
Diffuse grainy Scl-70 dc SSc
Centromeric Centromere Lc SSc
Nucleolar PM/Scl, RNA-pol1, U1RNP SSc, SLE, SS
Speckled cytoplasmic Jo-1, SRP, Mitochondria PM/DM/PBC
Diffuse cytoplasmic Ribosome SLE
57. What titre?
• Widely accepted cutoff - 1:40
• Up to 30% of healthy persons, usually elderly and female or relatives
of people with CTDs may have positive ANA
• A POSITIVE SCREENING ANA OF ANY TITER REQUIRES CLINICAL
COORELATION
58. What after ANA is positive and significant??
• Test for Anti-extractable nuclear antigen antibodies depending on
clinical scenario
59.
60. What do different Antibodies mean in SLE??
• Anti- dsDNA : Renal disease and overall disease activity
• Antiribosomal P:neuropsychiatric manifestations and renal disease
• Anti Ro and anti LA: cutanaeous and neonatal lupus
• Anti-Sm-:specific for SLE without clinical disease manifestation
correlation
61. What about Systemic Sclerosis?
• Anti- centromere: CREST
• Anti- Scl 70 and anti- RNA polymerase3: dcSSc and pulmonary
fibrosis
• Anti-PM-Scl: Myositis- SSc overlap
62. Can anti-ENA be positive with ANA being
negative??
YES
• Some antigens are relatively scarce in cell substrate like SSA/Ro and Jo-1 hence
ANA may be negative even though antibodies are present in serum
• So if clinical findings are highly suggestive – anti- ENA testing should be done
63. Anti-Neutrophil cytoplasmic antibodies
• Antibodies directed against certain proteins in the cytoplasmic
granules of neutrophils and monocytes
• Two step testing-
• First, Indirect fluorescent antibody detects ANCA
• Second, if ANCA is positive, ELISA testing is done for presence of specific
antibodies against Proteinase- 3 or Myeloperoxidase
65. C- ANCA
• diffuse,granular cytoplasmic staining pattern observed by
immunofluorescence microscopy.
• Proteinase-3 is the major c-ANCA
• Reference range: Absent or titer less than 1:120
66. How to Interpret c-ANCA?
• In proper clinical context, c-ANCA is 98% sensitive and specific for
Granulomatosis with polyangiitis
• In patients with limited disease, with atypical presentation- sensitivity
drops to 60%
• In patients with positive c-ANCA- level of titer elevation DOES NOT
indicate activity of disease
67. P- ANCA
• Localized perinuclear or nuclear staining pattern
• Major target antigen is Myeloperoxidase
• Other targets like elastase, cathepsin G, Lactoferrin etc are not
convincingly associated with vasculitis
68. What does positive p-ANCA mean?
• p-ANCA pattern on immunoflorescent microscopy is always followed
by ELISA for antibodies against myeloperoxidase as other antigens can
give p-ANCA positive but are not clinically significant
• Anti-myeloperoxidase antibodies are positive in 75% of patients with
Microscopic polyangiitis and 48% of those with eosinophilic
granulomatosis with polyangiitis
69. Synovial fluid analysis
• Useful mainly in ACUTE MONOARTHRITIS
• Synovial biopsy may be useful in PERSISTENT MONOARTHRITIS
70.
71. HLA B27
• Associated with spondylo-arthropathies
• HLA B27positive itself does not mean disease Can be positive in up
to 7 % of general healthy population
• Present with higher frequency in associated conditions, up to 50-90%
prevalence
73. Use of imaging
• Modalities available
• Radiography
• Ultrasonography
• CT scanning
• MRI
74.
75. Take Home Message
• Differential diagnosis of polyarthritis is wide.
• Differentiate inflammatory polyarthritis from non-inflammatory polyarthritis on history
and examination.
• Use Pattern recognition approach to arrive at clinical possibilities.
• Start investigations by more sensitive tests which if positive, should then be followed by
more specific tests to confirm the diagnosis.
• Never interpret lab results without knowing clinical context.
• “ Arthritis Panels” or “Rheumatology Panels” have no useful meaning.
