1. Extra-articular manifestation
1.1. Increased risk of infections
1.2. Gi hemorrhage/ perforation
1.3. Vasculittis (Leukocytoclastic vasculitis
1.4. Amyloidosis
1.5. Sublaxation of cervical spine
2. Pathogenesis
2.1. No exact etiology
2.2. due to immune tolerance
2.3. multiple factors
2.3.1. hereditary
2.3.1.1. Increased risk in first degree family members
2.3.1.2. high in monozygotic twins 30%
2.3.1.3. certain alleles present in HLA II predispose to RA
2.3.1.3.1. DR1
2.3.1.3.2. DR4
2.3.1.3.3. DR10
2.3.1.3.4. DR14
2.3.1.4. These alleles are part od HLA-DRB1 gene
2.3.1.5. gene PTPN 22 is associated with RA
2.3.2. immune system
2.3.2.1. humoral
2.3.2.1.1. RF
2.3.2.2. cellular
2.3.2.2.1. T lymphocytes
2.3.2.2.2. B-lymphocytes
2.3.2.2.3. Other leukocytes
2.3.3. Environmental
2.3.3.1. Infectious Agents
2.3.3.1.1. intiators of disease
2.3.3.1.2. Viruses
2.3.3.1.3. Bacteria
2.3.3.2. Smoking
2.3.3.2.1. citrullinated proteins can cause strong activation of immune system
2.3.4. local
2.3.4.1. Mainly mediated by
2.3.4.1.1. macrophages
2.3.4.1.2. synoviocytes
2.3.4.1.3. cytokines
2.3.4.1.4. growth factors
3. Morphologic pathology
3.1. Joints
3.1.1. Synovium thickening, edematous and hyperplastic
3.1.2. Infiltration of perivascular inflammatory cells with lymphoid aggregates
3.1.3. Fibrin aggregation covering synovium & present in joint space (rice bodies)
3.1.4. Accumulation of neutrophils on the synovial surface and fluid, but not deep in stroma
3.1.5. Osteoclastic activity
3.1.6. Pannus Formation
3.1.6.1. Mass of synovium, stroma, granulation tissue and inflammatory cells
3.2. Skin
3.2.1. Rheumatoid nodules (Seen in other organs too)
3.3. Heart
3.3.1. Myocarditis
3.4. Blood vessels
3.4.1. Rheumatoid vasculitis
4. A chronic systemic inflammatory disorder that principally affects multiple joint and may affect many tissues and organs
4.1. Joint involvement is characterized by non-suppurative and destructive inflammatory synovitis
5. Clinical Features
5.1. 1-2% of adults
5.2. Female more than male
5.3. 40-70 years old
5.4. Diagnosis
5.4.1. based on criteria
5.4.2. on pattern of joint involvement, duration of symptoms, lab values (ESR, RF, CRP, ACPT)
6. Development of Limbs
6.1. Intraembryonic mesoderm
6.1.1. paraxial mesoderm
6.1.1.1. Most medial
6.1.1.2. Somites
6.1.1.2.1. at the end of 3rd week
6.1.1.2.2. differentiate
6.1.1.2.3. appear as elevations lateral to neural tube
6.1.1.2.4. develop craniocaudally
6.1.2. intermediate mesoderm
6.1.3. Lateral mesoderm
6.1.3.1. Somatic/ parietal layer
6.1.3.1.1. body and limbs are formed by the overlying ectoderm
6.1.3.2. visceral/ splanchic
6.1.3.2.1. wall of GIT with underlying endoderm
6.1.4. Mesodermal cells differentiate into mesenchymal cells
6.1.4.1. fibroblast
6.1.4.1.1. blood vessels
6.1.4.1.2. connective tissue
6.1.4.2. chondroblast
6.1.4.3. osteoblast
6.2. Early stages
6.2.1. Week 4
6.2.1.1. Limb buds (venterolateral region)
6.2.1.1.1. day 26-27
6.2.1.1.2. day 27-29
6.2.1.1.3. composed of
6.2.2. Week 5
6.2.2.1. Hand and foot plates on day 32/36
6.2.2.2. Mesenchymal condensation form
6.2.2.2.1. mesenchymal models of the bone
6.2.2.3. chondrification centers appear
6.2.2.4. Motor axons from spinal cord enter limb buds
6.2.3. Week 6
6.2.3.1. Digital rays appear of the hand
6.2.3.1.1. Mesenchymal condensation
6.2.3.1.2. AER at the tips of the digits induce the bone formation (phalenges)
6.2.3.1.3. regions between the digital rays is loose mesenchymal
6.2.3.2. cartiliginous skeleton appears
6.2.4. Week 7
6.2.4.1. digital rays appear of the foot
6.2.4.2. osteogenesis of long bones begins (primary ossification centers)
6.2.4.3. Limbs extend ventrally
6.2.5. Week 8
6.2.5.1. Separate digits day 52/56
6.3. Late stages
6.3.1. Week 12
6.3.1.1. All long bones have primary ossification centers
6.3.1.1.1. form diaphysis
6.3.2. 1st year after birth
6.3.2.1. ossification of carpals begin
6.3.3. Synovial joints development begin in the 6th week and appear by the end of the 8th week
6.3.4. After formation of long bones, myoblasts aggregates on the limb buds and form MUSCLE MASS
6.3.4.1. seperated into dorsal (extensor) & ventral (flexor)
6.3.4.1.1. Upper limb muscles derived from the cervical myotomes
6.3.4.1.2. Lower limb muscles derived from the lumbosacral myotomes
6.4. Development of Cartilage
6.4.1. Mesenchyme
6.4.1.1. Mesenchymal condensation
6.4.1.1.1. chondrification centers Mesenchymal cells →chondroblasts
6.5. Bone formation/ ossification
6.5.1. Intramembranous
6.5.1.1. directly from mesenchymal cells
6.5.1.1.1. osteopregeneritor
6.5.2. endochondral ossification
6.5.2.1. within hyaline cartilage
6.5.2.2. Developing of cartilage model
6.5.2.2.1. mesenchymal cells form a cartilage model of the bone
6.5.2.3. Growth of the cartilage model
6.5.2.3.1. In length
6.5.2.3.2. In width
6.5.2.4. development of primary ossificiation centers
6.5.2.4.1. perichondriom lies down periosteal long collar
6.5.2.4.2. nutrient artery penetrates center of cartilage model
6.5.2.4.3. osteogenic bud brings osteoblasts and osteoclasts to center of cartilage model
6.5.2.4.4. osteoblasts deposit bone matrix over calcified cartilage forming spongy bone trabeculae
6.5.2.4.5. osteocyte form medullary cavity
6.5.2.5. development of secondary ossification centers
6.5.2.5.1. blood vessels enter the epiphyses around time of birth
6.5.2.5.2. spongy bone is formed but no medullary cavity
6.5.2.5.3. Formation of Articular Cartilage
6.6. Limb rotation
6.6.1. Limbs extend ventrally
6.6.1.1. Upper limb
6.6.1.1.1. laterally (90 degrees)
6.6.1.2. Lower Limb
6.6.1.2.1. medially 90 degrees
6.7. Nerve supply
6.7.1. Motor axons from spinal cord enter limb buds on week 5 & grow as dorsal and ventral muscle masses
6.7.2. sensory axons enter limb buds in guidance by motor axons
6.7.3. Neural crest cells (Schwann cells precursors) surround nerves in limbs & form myelin sheaths & neurolemma
6.7.4. Spinal nerves distribute as bands along the developing buds and migrate distally as the limb elongates (dermatomes)
6.8. Blood supply
6.8.1. Aorta
6.8.1.1. Intersegmental arteries
6.8.1.1.1. its branches supply the limb buds
6.8.2. in each limb
6.8.2.1. primary axial artery → peripheral marginal sinus → peripheral vein
6.8.3. Primary axial artery
6.8.3.1. Upper limb
6.8.3.1.1. arm
6.8.3.1.2. forearm
6.8.3.2. Lower limb
6.8.3.2.1. thigh
6.8.3.2.2. leg
6.9. Polarized development
6.9.1. generally
6.9.1.1. craniocaudal direction
6.9.2. transverse plane
6.9.2.1. mid-dorsal region
6.9.3. limbs
6.9.3.1. proximo-distally
6.9.4. amniotic fluid surrounding the embryo in the uterus assist in
6.9.4.1. symmetrical external growth
6.9.4.2. muscular developmen through movement
6.10. Pattern formation in the limbs
6.10.1. HOX gene
6.10.1.1. regulate the cranocaudally development of the limbs
6.10.2. ZPA
6.10.2.1. is a cluster of mesenchymal cells
6.10.2.2. regulates the anterio-posterior pattern development of the limbs
6.10.2.3. produces retinoic acid & Sonic hedgehog ??
6.10.3. forelimb
6.10.3.1. TBX 4
6.10.4. hindlimb
6.10.4.1. TBX 5
6.11. Limb Malformation
6.11.1. Ameila
6.11.1.1. complete absence of limbs
6.11.1.1.1. suppression in week 4
6.11.2. meromelia
6.11.2.1. partial absence of the limbs
6.11.2.1.1. disturbance of development in week 5
6.11.3. cleft hand or foot(lowbster claw)
6.11.3.1. absence of central digits
6.11.3.1.1. problem in msenchymal condensation
6.11.4. congenital abscence of the radius
6.11.4.1. failure of radial premordium to form
6.11.5. brachydactyl y
6.11.5.1. rare
6.11.5.1.1. shortness of fingers or toes
6.11.6. syndactyly
6.11.6.1. cutaneous
6.11.6.1.1. failure of web to degenerate between digits
6.11.6.2. osseous
6.11.6.2.1. failure of notches to develop between digits
6.11.6.3. hereditary
6.11.7. polydactyly
6.11.7.1. extra finger(s)
6.11.7.1.1. hereditary
6.11.7.1.2. medial or lateral of the hand but not the middle
6.11.7.1.3. lateral in the foot
6.11.8. congentical club foot/ talipes
6.11.8.1. abnormal position of the foot
6.11.8.2. Affected child walks on ankle
6.11.8.3. Talipes equinovarus (most common)
6.11.8.4. medial orientation and inversion
6.11.8.5. multifactoral inheritance or movement restriction
6.11.8.6. twice common in male
6.11.9. congenital dislocation of the hip
6.11.9.1. Causes
6.11.9.1.1. generalized laxity
6.11.9.1.2. abnormal development of the acetabulum
6.11.9.2. common in female more than males
6.12. Causes of the limb malformations
6.12.1. Genetic factor
6.12.1.1. trisomy 18
6.12.1.2. environmental
6.12.1.2.1. thaledomide
6.12.1.3. mutated gene
6.12.1.3.1. brachydactyly
6.12.1.4. Multifactorial inheritance
6.12.1.4.1. congenital dislocation of the hip
6.12.1.5. vascular desruption
6.12.1.5.1. amniotic bands