Osteoarthritis & Chronic Inflammatory Arthritis

Question 1

Impact of Arthritis

Answer 1

• 1 out of 5 US adults carries diagnosis of arthritis (52 million)
  
  • Most common is osteoarthritis (degenerative)
  • Other forms : RA, lupus, gout
• 2/3 individuals with arthritis are <65 yo
• More common among women (26%) vs men (19%)
• $128 billion in medical expenditures/lost earnings in 2003

Question 2

Osteoarthritis (OA)-aka Degenerative Arthritis-General (1/2)

Answer 2

• Characterized by DEGENERATION (wear and tear) of articular cartilage
  
  • **Distinct from an inflammatory arthritis
  • Chondrocytes of articular cartilage respond to biomechanical and biologic stresses in way that results in breakdown of matrix
• Most common type of arthritis
• Classified as primary or secondary
  
  • Primary most common
  • secondary-see with trauma (knee or shoulder)

Question 3

Secondary OA

Answer 3

• several ways to develop
  
  • **trauma
  • inflammatory arthritis
  • dysplastic and hereditary conditions
  • Kashin-Bek dz
  • bone disorders
  • metabolic and endocrine disorders

Question 4

Osteoarthritis (OA)-aka Degenerative Arthritis-General (2/2)

Answer 4

• Seen most commonly in persons >65 yo
• Radiographic changes
  
  • >45 yo: knee 37%, hip 27%, hands >90%
  • Most with radiographic changes have few sx
• **Symptomatic OA (lower #s)
  
  • >45 yo: 17% knee, 9% hip
• Lifetime risk of symptomatic OA of knee: 66%
  
  • Higher with obesity and risk factors

Question 5

OA/DA: Pathogenesis-RF

Answer 5

• *Age=strongest RF*
• Obesity most associated with OA of the knee but may contribute to hip & hand
  
  • Leptin may have influence on chondrocytes
• Chronic repetitive impact loading
  
  • Long term weight bearing sports
• Genetic factors (if gma has bony nodules)
  
  • Many have family history, especially finger involvement in women
• Jt dysplasia increases risk for hip OA

Question 6

Nml Morphology (3+1 main players)

Answer 6

• Specialized connective tissue
  
  • Collagen, proteoglycans, water, chondrocytes
• Collagen: Mostly type II collagen
  
  • Distributes compressive forces
  • Tethers cartilage to subchondral bone
  • Dissipates weight bearing force, protecting soft tissue & subchondral bone
• Proteoglycans=cushion
  
  • Aggrecan: high fixed negative charge allows for retention of water
• Chondrocytes mediate turnover of matrix components
  
  • Sparsely scattered
  • Chondrocytes influenced by factors ie) GF, cytokines, physical stimuli

Question 7

OA/DA Morphology

Answer 7

• Articular cartilage
  
  • Loss of homogeneity, disruption & fragmentation of surface
• Deeper layers of cartilage invaded by capillaries from calcified cartilage
• Chondrocytes which are normally isolated cells now proliferate & cluster
• Osteophytes form (bone spurs)
• **Early OA: WATER content of diseased cartilage INCREASES & cartilage swells
• Increase in both anabolic (build up) & catabolic (break down) activity
  
  • Eventually, anabolic cannot keep up with catabolic activity
  • Degradative enzymes released by chondrocytes
  • Matrix less structurally sound & less organized; cannot withstand forces
• Causes for biochemical & metabolic changes not fully understood

Question 8

OA/DA Clinical Characteristics

Answer 8

• Localized joint pain
• Stiffness
• Worse with weight bearing-after activity or at the end of the day
• Better with rest
• Very little morning stiffness (diff from other)
• Distal & Proximal interphalangeal joints
  
  • Heberdens & Bouchards nodes
• Knees, Hips, Cervical & lumbar spine
• Joint crepitus-crunching
• Swelling not common
• Bony enlargement

Question 9

OA: Xrays and Labs

Answer 9

• Xrays
  
  • Decreased joint space
  • Subchondral sclerosis (bones start touching) & cysts
  • Osteophytes (spurs)
  • ***xray findings may not always be proportionate to pain
• Labs
  
  • No useful tests
  • Not inflammatory

Question 10

OA/DA: Early and Late Stages

Answer 10

• losing the dark line (joint space) and joint connections starting to get misaligned

Question 11

OA/DA Management

Answer 11

• No cure
• Manage risk factors: physical therapy, exercise, weight loss, dietary measures
  
  • Quadriceps strengthening in knee OA
• Pharmacologic (pain control)
  
  • Acetaminophen, Nonsteroidal anti-inflammatory drugs & other analgesics
  • Intra-articular steroid injections in selected cases
• Sx: Jt replacement (especially knees, hips-large jts)

Question 12

RA General

Answer 12

• Systemic
• Chronic (>6wks, some infections can mimic-Parvovirus B19)
• Inflammatory
• Autoimmune-WBC attacks jts
• Primarily involves jts but can affect extra-articular organs
  
  • Lungs (interstitial lung disease, pleural effusion)
  • Anemia of chronic disease
  • Eyes (episcleritis, scleritis)
  • Skin (vasculitis), soft tissue (rheumatoid nodules)
  • Heart (pericarditis)
  • CNS v. rarely (pachymeningitis), peripheral neuropathy (v. severe)

Question 13

RA-Epidemiology and RF

Answer 13

• Prevalence: 1%
• 5 times more common in women vs men (duh, a.i. dz)
• Peak incidence 2nd-5th decade of life
• Genetic risk factors: HLA-DRB1 locus (MHC-Class 2)
  
  • Genetic susceptibility
• Environmental risk factors
  
  • Potential triggers: infectious (P gingivalis and others)
    
    • Prevalence of periodontal disease 2 fold amongst RA
  • Smoking: anti-CCP Ab (cyclic citrullinated peptide)-MAKE MORE!
    
    • Relative risk 1.4 for developing RA compared to nonsmokers

Question 14

**RA vs. OA/DA**

Answer 14

• Inflammatory (swelling) VS. OA/DA-no swelling
• Prolonged morning stiffness VS. OA/DA: limited morning stiffness
• Systemic manifestations VS. OA/DA: localized symptoms
• Joints involved:
  
  • PIPs, MCPs, wrists VS OA/DA: PIPs, DIPs, CMCs
• Lumbar spine not involved VS. DA lumbar spine commonly involved

Question 15

Morphology: RA vs. OA

Answer 15

• sides, where synovium joins up with bone-inflamm is fom jt space lining
• RA:**eroding cartilage
• OA/DA: **bony spur; more evenly thoughout

Question 16

RA Pathogenesis

Answer 16

• (over) Activation of CD4+ helper T cells
  
  • Environmental trigger in genetically predisposed individual
• T and B cell responses to self-Ag
  
  • Activated CD4+ helper T cells, TH17 cells, B lymphocytes & plasma cells, macrophages
  • Inflamed synovium
  • ***Increase in inflammatory cytokines:
    
    • IL1, IL6, TNF, IL8, IL17, IFN gamma
• Fibroblasts, chondrocytes, synovial cells respond to pro-inflammatory milieu
  
  • Destructive enzymes: collagenase, stromelysin, elastase, PGE2
• **Osteoclast response
  
  • Increased expression of **RANKL (receptor activator of nuclear factor kB ligand)
  • Osteoclast activation leading to bone erosions
    
    • ​want to get to the pt before the bony erosions happen

Question 17

RA Morphology: Pannus Formation (5-LEDTV)

Answer 17

• Chronic papillary synovitis
• Synovial cell hyperplasia & proliferation: THICKENED=pannus
• Perivascular inflammatory cell infiltrates: DENSE
  
  • CD4+ T cells, plasma cells, macrophages
• Angiogenesis: VASCULAR
• Neutrophils & organizing fibrin on synovial surface: LAYERED
• Increased osteoclast activity: ERODED
  
  • ​arrows on the X-ray

Question 18

RA X-rays

Answer 18

• periauticular osteopenia-darker due to osteoclast activation
• bone is getting thinner as it gets closer to joints
• on right, not seeing bones that were previously seperated by bone spaces in wrist

Question 19

RA Diagnosis

Answer 19

• Clinical Diagnosis
  
  • Chronic, symmetrical, inflammatory polyarthritis
  • Extra-articular manifestations may occur
    
    • Rheumatoid nodules, Interstitial lung disease
      
      • nodule: in area where theres lots of trauma/friction (elbows, hands)
      • area of fibrinoid necrosis (ctr) surrounded by palisading histiocytes (arrows)
• Blood tests
  
  • Rheumatoid factor
    
    • Auto-Abs against Fc portion of normal polyclonal IgG
    • IgM, IgG, or IgA
  • Anti-CCP Ab-increased in smokers
  • Elevated inflammatory markers (sedimentation rate, C-reactive protein-made by liver)
• X-rays
  
  • Erosions and peri-articular osteoporosis
• Synovial fluid
  
  • Inflammatory (look for elevated #wbc), low glucose, nonspecific

Question 20

RA Tx (1/2)

Answer 20

• Try to get to the root of the inflamm
• NSAIDS
  
  • Often not enough as monotherapy
• Corticosteroids (prednisone)
  
  • As a bridge
  • Too many SE to use as monotherapy
• DMARDS (disease modifying anti-rheumatic drugs)
  
  • Mainstay longterm tx
  • Mostly immunosuppressive
• Non-biologic DMARDs
  
  • Methotrexate (immunosuppresive)
  • Leflunomide
• Also, biologic….

Question 21

RA Tx-2/2: Biologics

Answer 21

• decreases the rate of the deformities-much more aggressive and immunosuppressive
• aims for those stupid IL that are causing all the trouble
• Anakinra
  
  • Anti-IL1
• *****Etanercept, Adalimumab, Infliximab-most effective, and have the most data
  
  • Anti-TNF alpha
• Tocilizumab
  
  • Anti-IL 6
• Abatacept
  
  • CTLA4 agonist
  • Blocks CD28 co-stimulation of T cells
• Rituximab-also used for NHL chemo and SLE
  
  • Anti-CD20
  • Causes destruction of B cells
• Tofacitinib (oral)
  
  • JAK1 and 3 inhibitor
  • Janus associated kinase
  • Blocks signaling for inflammatory cytokines

Question 22

Seronegative Spondylo-Arthropathies: General

Answer 22

• Ankylos = Greek for “bent,” fusion (**can get fusion of the spine)
• Spondylos = Greek for “vertebral disk”
• Group of inflammatory arthritides (cousin to RA) which primarily involve ankylosing of the spine
  
  • Inflammatory back pain
  • Improves with exercise, not relieved by rest
• Different pattern of joint involvement compared to RA
  
  • Oligoarticular (<3), assymetric, more large joints involved
  • Axial involvement: sacroiliitis (upper buttock pain, worse in the morning, associated with stiffness)
    
    • “bamboo spine” (not seen in RA)
  • Enthesitis = inflammation of tendon insertions (not seen in RA)
    
    • Ex: achilles tendon
• Extra-articular manifestations
  
  • Uveitis (not seen in RA)
  • GU tract (in reactive)
  • skin (in psoriatic)
  • GI tract (in IBD associated)

Question 23

Seronegative Spondylo-Arthropathies: Umbrella

Answer 23

• Psoriatic arthritis
  
  • peripheral psoriatic arthritis in 15-30% pts with psoriasis
  • over spondyloarthritis in 10% of pts with psoriatic arthritis
• Ankylosing spondylitis-bamboo spine, fusion
• Inflammatory Bowel Disease (IBD) related-Crohns or UC (5-10%)
• Reactive Arthritis
  
  • triad: cant pee, cant see, cant climb a tree
    
    • nongonococcal urethritis, conjunctivitis, arthritis
    • though many only have arthritis
  • more temporary: self-limiting over 4-12 mo
    
    • ​10-20% develop chronic
  • Keratoderma blennorhagica (pic)
  • follows certain enteric infections and STI
• usually from infections
• Formerly known as Reiter Syndrome
• Undifferentiated spondyloarthropathy-less specific

Question 24

Seronegative Spondylo-Arthropathies: Epidemiology

Answer 24

• 346 - 1,310 per 100,000 among persons 25 years and older in US
• HLA B27
  
  • Allele of MHC I (or HLA Class I)
  • 90% of white pts with AS, 50% of AA with AS
  • 60-70% in psoriatic or IBD related spondyloarthropathy
  • 7-9% of healthy pop
    
    • ​therefore, use this test cautiously
• Typically age 16-30 years (younger age group than RA)

Question 25

Seronegative Spondylo-Arthropathies: Path Theory 1/2

Answer 25

* Arithrogenic theory AKA “**Molecular Mimicry**” * \*\*Yersinia, Shigella, Salmonella, Campylobacter, Chlamydia

Question 26

Seronegative Spondylo-Arthropathies: Path Theory 2/2

Answer 26

* **Misfolding & dimerization** hypothesis * Unrelated to antigen presentation * Tendency to misfold & form dimers * Leads to inappropriate stimuli & inflammation * Homodimers * TNF a induction * Direct activation of NK cells, dendritic cells & CD4 T cells * CD4 T cells then produce **IL-17 + IL-23 (**vs. IL1,6, TNF a)

Question 27

Seronegative Spondylo-Arthropathies: Path Factors

Answer 27

* TNF a plays a role * Similar to RA * IL-17, IL-23, TH 17 cells also play a substantial role * Different from RA * \*\*\*IL- 17 * **Important role in defense against extracellular bacteria** * **Dysregulated expression leads to joint destruction** * Increase in *proinflammatory cytokines* * Increase in *metalloproteinase* * Increase in *RANKL activity* * IL-23 * Strongly overexpressed in gut of AS patients * Promotes highly specific entheseal inflammation

Question 28

Seronegative Spondylo-Arthropathies: Sacroilitis

Answer 28

* Granulation tissue from inflammation erodes through bone & cartilage into joint cavity * Synovial hypertrophy * Infiltration of subsynovium: macrophages, lymphocytes, plasma cells * Advanced disease: * Erosion of bone * Cartilage fusion (loss of joint space) * Sclerosis (increased whiteness) in para-articular bone * Osteoblast activation eventually leads to replacement of cartilage by new bone-\>AKA ankylosis

Question 29

Spinal Ankylosis

Answer 29

* Two important processes: * 1. Spinal inflammation * 2. Spinal ankylosis * Inflammation at **vertebral corners** & subsequent development of **syndesmophytes** * Evidence for link between both * But also evidence that osteoproliferation may not be completely dependent on inflammation

Question 30

Syndesmophytes

Answer 30

* Sclerosis & squaring of vertebral corners * Syndesmophytes leading to complete briding ossification

Question 31

Seronegative Spondylo-Arthropathies: Diagnosis

Answer 31

* Inflammatory back and/or buttock pain * Chest wall pain * due to costo-sternal jt (ribs joining sternum) * Enthesitis (ie Achilles tendon, plantar fascia) * Dactylitis: sausage shaped swelling of digit caused by flexor tenosynovitis-ENTIRE finger (not just jt) * Extra-articular: uveitis (25-30% of pts) * Sacroiliitis on imaging (MRI or xray)

Question 32

Seronegative Spondylo-Arthropathies: Tx

Answer 32

* Education & Physical Therapy * NSAIDs * Limitations, especially with underlying IBD * Oral DMARDS (dz modifying anti-rheumatic drugs) * Sulfasalazine, methotrexate * Biologic Therapies * \*\*\***Anti-TNF a**--cant use the other antis that RA uses * Adalimumab, Etanercept, Infliximab * **Anti-IL 23**/ IL 12 * Ustekinumab * Anti-IL17 in development * Ixekizumab, Sekukinumab (clinical trials in psoriasis)