Rheumatoid Arthritis

Prof Dr Ahsan Kazmi

Pathology Department
Al Nafees Medical College, Islamabad
  A chronic, systemic, inflammatory
disorder
 Affect many tissues and organs e.g,
Rheumatoid  Skin,
Arthritis (RA)  Blood vessels,
 Heart,
 Lungs and
 Muscles
  Principally attacks the joints producing a
non- suppurative proliferative synovitis
Rheumatoid
 Progresses to
Arthritis (RA)  Destruction of the articular cartilage
 Ankylosis of the joints
 1% world population affected
Epidemiology Women to men ratio 3-5:1
Peak age 40-70 yrs
  Cause remains unknown but autoimmunity plays a
pivotal role
 Currently believed:
The Etiology
RA is triggered by exposure of an
immunogenically susceptible host to an
arthritogenic microbial antigen
  One of the leading theories:
The  an infectious agent

Pathogenesis  may induce an autoimmune response

of RA  by molecular mimicry between a T cell epitope

of the infectious agent and a self-component in
the joint
  Genetic susceptibility
 a first-degree relative of RA patient has about a 16-
fold increased risk of acquiring the disease compared
The with the general population
Pathogenesis  Studies of monozygotic twins have shown a
of RA concordance rate between 15% to 30%, which is
approximately 4 times greater than the rate in
dizygotic twins.
 The severity of rheumatoid arthritis
 involves multiple genes

 The Best understood genes - that encode class II

The Major Histocompatibility Complex (MHC) molecules
Pathogenesis
 MHC alleles may account for approximately 30% of
of RA
the genetic risk of severe rheumatoid arthritis

 The most severe, erosive disease is associated with

HLA-DR4 alleles
 RA linked to specific HLA-DRB1allels
Rheumatoid arthritis (RA) alleles
The  15 different alleles
Pathogenesis  The most prominent are called HLA-
DRB1*0401/0404 and HLA-DRB1*0101/0102
of RA alleles
Also linked to PTPN22 tyrosine phosphatase that
regulates the T cell activation
  Environmental Arthritogen

 Microbial triggers e.g, EBV, retroviruses,

The mycobacteria, Borrelia, and Mycoplasma
Pathogenesis implicated but not proved
of RA
 Smoking: host proteins modified by conversion
of arginine to citrulline by smoking can induce
robust response in some pts
Key diagram
  Once an inflammatory synovitis is initiated
 CD4+ autoimmune response may be propagated by
autoimmunity to type 2 collagen and
glycosaminoglycans, with continued activation of
CD4+ TH1 and TH17 cells.
Autoimmunity
 Abs against citrulline (-modified peptides) are
present in many RA pts  chronicity
 Autoantibodies to RAF also occurs in 80% of RA pts
 These are good markers of disease activity
  Tissue damage occurs through cytokines produced
by CD4+ T cells that coordinate an ongoing response
 These include:
 Interferon gamma and IL-17 which act on
The macrophages and synoviocytes including those
cells which produce host of mediators:
Pathogenesis  (e.g, IL 1,6,23, PGE2, TGF β) and especially TNF
of RA  that can drive RANKL expression and
osteoclastogenesis as well as synoviocyte
hyperplasia

(RANKL- Receptor activator of nuclear factor kappa-Β ligand. Affect

the immune system and control bone regeneration and remodeling)
  Cartilage Destruction by:
The  Local production of matrix metalloproteinases
Pathogenesis
of RA  Immune complex activation of complement and
neutrophils
The
Pathogenesis
of RA
  Synovium, the lining of diarthrodial joints, is the
The Normal tissue initially affected in the various forms of
chronic inflammatory arthritis.
Synovium  Normal synovium consists of only two or three layers
and the RA of lining cells on a stroma of connective tissue.
Synovium  The cellular types have macrophage and fibroblast
like features
The Normal
 Highly vascular tissue that normally generates small
Synovium amounts of synovial fluid - nourishing and
and the RA lubrication for hyaline cartilage
 In the various forms of chronic inflammatory
Synovium arthritis, the synovium is the “target lesion”
  Diseased synovium shows
The Normal  Villous hypertrophy,
Synovium  Surface fibrin deposits,
and the RA  Vascular proliferation,
 Lymphoplasmacellular infiltrates, and sometimes
Synovium  Pseudolymphoid follicles
The Normal  The CD4+ T cell is a major infiltrating cell in the
synovial lesion in RA and other types of chronic
Synovium inflammatory arthritis
and the RA  Plays a central role in the pathogenesis of these
Synovium diseases
 Pannus
 The diseased synovial tissue is called pannus
The Normal  Pannus  hypertrophied synovium
Synovium  Releases proteinases that lead to
and the RA  Erosions in the cartilage
 Disruption of the periarticular
Synovium structures (Ligaments)
 Joint instability
  Gross appearance
 Early stages-
 Synovium edematous and hyperplastic
Morphology-  Showing delicate and bulbous fronds

Joints  Later stages-

 pannus of prolif. synov, inflam cells & fibroblasts
encroach on the hyaline carti  destruction
 Pannus can bridge apposing bones to form a
fibrous ankylosis  ossification
 Microscopic
 Dense perivascular, mononuclear, inflam
cell infiltrate with focal lymphoid
aggregates
Morphology-  Neutrophils accumulate on syn surface
and in synovial fluid
Joint  Vasodilatation & vascular permeability is
reflected by hemosiderin deposits and
aggregates of organizing fibrin
 Osteoclast activation bone erosion
osteoprosis & sub chondral cysts
 Gross
 Rhumatoid nodules are firm non-tender arising
in subcut., tissue in 25% pts
 Typically at pressure points e.g , elbows
 Also in lungs, spleen heart valves, aorta, and
Morphology- other viscera
Skin
Microscopic:
Lesions show a central zone of fibrinoid necrosis,
surrounded by a palisade of activated
macrophages
Morphology-  Pts with severe disease and high titres of RA factor
at a greater risk of developing small to medium sized
Blood vessels vessel vasculitis comparable to poly arteritis nodosa
  Bilat symmetrical involvement
 Since the synovium is the target lesion, joints lined by
Clinical synovium are affected
Features  The small joints of the hands are particularly
affected, including the MCP and PIP joints; the DIP
joints tend to be spared.
  The high cervical spine at C1-2 is affected, with the
potential for “pithing” of the spinal cord.
 (The odontoid is lined by synovium, and forms part
Clinical of C2; the C1 ring surrounds the odontoid and is
reinforced by ligaments; pannus formation at the
Features odontoid can potentially disrupt the C1-C2
articulation, and lead to severing of the spinal cord at
this level.)
  The elbows, knees, hips, ankles and foot joints are
also commonly affected.
Clinical  The thoracic and lumbar spines are not typically
affected directly by RA since
Features  there is very little synovium present in the facet joints of
the lumbar and thoracic spines
Clinical
Features
 a. Symmetric involvement of second/third
metacarpophalangeal (MCP) and PIP joints
(1) Produces ulnar deviation, morning stiffness
Clinical (2) Swan neck deformity
findings (a) Flexion of DIP joint
(b) Extension of PIP joint
(3) Hoiitonnicre deformitv
RA gross
Clinical
Features
  Is extremely variable
 Begins insidiously with malaise, fatigue and
Clinical generalized musculoskeletal pain and then joint pain
Course  Small joints are usually affected first
 Involved joints are swollen, warm, painful and stiff on
arising or following inactivity
  Disease course may be
 slow or rapid

Clinical course
 Pts. may enjoy periods of
partial or complete remission
 a. Positive serum antinuclear antibody (ANA) test
(30%)
b. Positive serum RF (70-90%)
c. Normal to increased serum C3
Laboratory d. Decreased synovial C3
findings in RA e. Increased serum total protein
(1) Due to increase in y-globulins (IgC) in chronic
inflammation
(2) Polyclonal gammopathy on serum protein
electrophoresis
  No specific lab tests are diagnostic as pts.
Laboratory  Anemia:

Features of A normochromic, normocytic anemia may be

present, due to diminished erythropoesis seen with
RA acute and chronic inflammatory states.
  Acute phase reactants
Laboratory Increased levels of acute phase reactants (ESR, CRP,
Features of haptoglobin, ferritin, platelets) is common, and
RA considered a diagnostic marker by the American
College of Rheumatology (ACR).
  Liver and Kidney Function Tests
Laboratory  Abnormalities may occur as a result of medications used to
Features of treat RA but
 disease manifestation within the kidney and liver itself is
RA uncommon
Rheumatoid  Over 80% of patients with RA possess measurable
levels of rheumatoid factor, usually IgM, which is an
factor antibody directed against the Fc portion of IgG
  It is not considered to be diagnostic of RA since it can
be found in other inflammatory states (chronic
infections like TB and endocarditis) and in diseases
Rheumatoid where there is polyclonal stimulation of B cells.
factor  It is also present in about 15% of the normal
population over age 65.
  Synovial fluid analysis in RA is characterized by
inflammatory joint fluid with white cell counts
The synovial usually greater than 2000 cells/mm3.
fluid  Mostly neutrophils (as opposed to the predominant
round cell infiltrate seen in the synovium).
  The synovial fluid in RA patients is usually cloudy
or yellow (normal synovial fluid is clear)

The synovial
 The joints of many patients with RA have palpable
fluid effusions, which contain large amounts of synovial
fluid produced by the diseased synovium.
 Prognosis
 Most pts. have progressive disease
 RA reduce life expectancy by 3-7 years
Rheumatoid
 Death due to
Arthritis (RA):  Complications, e.G. Systemic amyloidosis & vasculitis
 Effects of therapy, e.G. GI bleeding related to long-term use
of anti-inflammatory drugs
 Infections from steroid use
RA vs OA
Infectious Arthritis
 Joints can be seeded through blood or by direct extention.
Thank you