Chapter 68: Arthritis Flashcards
Define osteoarthritis:
The aberrant repair and eventual degradation of articular cartilage in association with alterations in subchondral bone metabolism, periarticular osteophytosis and a variable degree of synovial inflammation
What percentage of adult cats/dogs have OA?
- 60% adult cats
- 20% adult dogs
What factors contribute to an individuals susceptibility to OA?
- Genetics
- Age
- Systemic factors (eg obesity)
How do chondrocytes change as they age?
- Synthesize smaller, less uniform aggregan molecules and less functional link proteins
- Mitotic and synthetic activities decline
- Responsiveness to anabolic mechanical stimuli and growth factors decreases
What is C-terminal truncation of aggregans?
An aging process in which length and uniformity of aggregan molecules is diminished
- Shorter molecules contain fewer chondroitin sulfate side chains but greater quantities of keratin sulfate
- Therefore, have less ability in imbibe water reducing the compressive stiffness
How does obesity predispose to the formation of OA?
How much more likely were dogs fed ad lib vs 25% less fed over their lifetime?
- Increases load on the joints
- Alters joint alignment - Focal overloads
- Causes a systemic subclinical proinflammatory state with increased circulating adipokines such as TNF, IL-6 and leptin
TNF and IL-6 have a role in degradation of articular cartilage
Dogs fed ad lib were 2x as likely to get OA
What are the three overlapping stages of articular cartilage changes with OA?
- Extracellular matrix degrades, water content increased, size of aggregan molecules decreased and structure of collagen network is damaged leading to reduced stiffness
- Chondrocytes try to compensate through enhanced proliferation and metabolic activity. Cell clusters appear surrounded by newly synthesized matrix molecules.
- Chondrocytes are no longer able to keep up, resulting in complete loss of cartilage tissue
Phase 1/2 - thickness, swelling as proliferate -> phase 3 lose the battle and thins away
What inflammatory cytokines are known to upregulate the synthesis of matrix metalloproteases (MMPs) and other proteolytic enzymes?
IL-1
IL-17
IL-18
TNF-a
Synthesis of tissue inhibitors of metalloproteinases (TIMPS) are concomitantly decreased
What role does COX play in OA?
Chondrocytes from human OA cartilage explants express COX-2 and spontaneously produce PGE2
- PGE2 decreases proteoglycan synthesis and enhances degradation of aggrecan and Type II collagen
- Upregulation of MMP-13, disintegrin and ADAMTS-5
- Downregulation of MMP-1
What role does nitrous oxide (NO) play in OA?
NO is a major catabolic factor produced by chondrocytes in response to proinflammatory cytokines IL-1b and TNF-a
- Promotes chondrocyte apoptosis, most likely via mitochondrial dysfunction
What enzymes are known to degrade aggrecan, a very early event in canine OA?
MMP-13
Aggrecanases (ADAMTS-4, ADAMTS-5)
What enzymes can degrade the triple helix of Type II collagen?
MMP-1 and MMP-13
maybe MMP-8 and MMP-14
What is the most abundant noncollagenous protein in articular cartilage?
Cartilage oligomeric matrix protein
What growth factors can stimulate aggrecan and collagen synthesis?
IGF-1
IGF-2
TGF-b
What is the synovium?
A discontinuous layer of fibroblast-like and macrophage-like cells that lines the joint capsule
It is the key tissue in OA pain
It is called the synovial membrane but it is not a membrane
What cell is a key cell in driving synovial control of cartilage metabolism?
Macrophages (through release of catabolic cytokines IL-1b and TNFa)
What cells are the precursors of osteophytes?
Mesenchymal stem cells present in periosteum or synovial lining
What fibers are found in joint nerves?
What are silent nociceptors?
- Abeta-fibers
- Adelta-fibers
- C-fibers
**C-fibers are silent nociceptors because they do not respond to pain in the normal joint but do have hyperalgesia from mechanical stimuli in inflamed joints
What enzyme plays a role in central sensitisation?
COX enzymes
COX inhibitors can prevent establishment of central sensitization
What imaging method can detect differences in glycosaminoglycan content in articular cartilage?
Gadolinium-enhanced MRI
What weight loss pharmaceuticals are licensed for use in dogs?
- Mitratapide
- Dirlotapide (also appetite suppressant)
Both are microsomal triglyceride transfer protein inhibitors
What are the expected cell counts and differential counts of normal synovial fluid, OA, rheumatoid, Nonerosive IMPA and Infective arthritis?
Normal joint: <2 x 10^9/L >94% mono
OA joint: 2-5 x 10^9/L >88% mono
Rheumatoid joint: 8-38 x 10^9/L 20-80% mono
Nonerosive IMPA: 4-370 x 10^9/L 5-85% mono
Infective arthritis: 40-267 x 10^9/L 1-10% monos (almost all neuts)
How does acetaminophen/paracetamol act on OA pain?
Unclear MOA:
Serotonin?
Central COX-1?
Works on Prostaglandin G2 and H2
What is the main cause of adverse events with NSAID use?
The inhibition of endogenous prostagladin production
- Endogenous PGE2 is important for maintaining gastric mucosal layer, quality of gastric mucous, mucosal blood flow and production of gastric acid.
What are some other side effects of NSAID use?
- Impaired platelet activity due to impaired thromboxane synthesis
- Bone marrow dyscrasias
- Thrombosis (PGI2 plays a role in prevention of thrombosis)
List some licensed NSAIDs, their class, their COX1:COX2 ratio and any important notes:
Carprofen
- Propionic acid derivative
- COX ratio 1:17 (COX-2 selective)
Deracoxib
- Coxib class
- Very high selectivity for COX 2
-Liver metabolism and fecal excretion with 1/5 urine
Etodolac
- indole acetic acid derivative
- mixed COX 1 and 2 to more COX 1 (nonselective)
- Can cause KCS
Firocoxib
- pyridylsulphone
- COX-2 specific, ratio 1: 342-430
Ketoprofen
- Propionic acid
- COX-1 selective
Mavacoxib (Europe)
- Preferential COX-2, ratio 1:21
- Therapeutic concentration maintained for 30 days (80d in 5%)
Meloxicam
- oxicam group
- COX-2 selective, ratio around 1:3
- Only one licensed in cats for long term
Phenylbutazone
- Slightly COX-2 selective, ratio 1: 2.64
Toxicities
Robenacoxib
- coxib class
- Highly COX-2 selective, ratio 1:140
- Persists longer at site of inflammation
Tepoxalin
- Non-selective COX inhibitor and inhibits 5-lipoxygenase (LOX)
- 10% GI adverse events
- Ameliorates collagen degradation in vitro
Tolfenamic acid
- analgesic and antipyretic
How frequently can intraarticular steroid injections be performed?
One injection every 6 weeks with no more than 3-4 per year per joint
What is the action of IM polysulfated glycosaminoglycan (adequan)?
- Inhibits cartilage oligomeric matrix protein degradation
- May also maintain chondrocyte viability or stimulate chondrocyte division
What are the actions of pentosan polysulphate (semi-synthetic GAG)?
- Slows down articular cartilage degeneration
- Stimulates synthesis of hyaluronan by synovial cells
- Stimulates synthesis of proteoglycan by chondrocytes
Structurally similar to heparin and has anticoagulant properties
What are the 2 principle essential FAs?
What FAs may be derived from these?
Linoleic acid and alpha-linolenic acid
From these can form:
- Arachidonic acid (n-6 FA)
- Eicosapentaenoic acid (EPA) n-3 FA
- Docosahexaenoic acid (DHA) n-3 FA
Involved in lipid transport and serve as precursors to eicosanoid hormone family, which regulates inflammatory processes
What 2 eicosanoid hormones produces from n-6 FAs (arachidonic acid) are considered key mediators of inflammation in OA?
PGE2 and LTB4 (leucotriene B4)
What is the most effective of the n-3 FAs (EPA or DHA)?
What actions does it have?
Eicosapentaenoic acid (EPA)
- reduces mRNA of cartilage degrading proteinases such as ADAMTS-4 and -5, MMP-3, MMP-13 and for COX-2
- dogs show 5.6% increased peak vertical force with high EPA diets
What is a significant genetic risk factor for ANA-positive IMPA?
DLA (dog leucocyte antigen) class II haplotypes
What is the best medium for a culture of synovial fluid?
Blood culture bottle
What will a synovial biopsy show with IMPA?
Infiltration of B- and T-lymphocytes, macrophages and neutrophils
What are the main types of nonerosive IMPA?
- Idiopathic groups I-IV
- Polyarthritis-polymyositis syndrome
- SLE and SLE-related disorders
- Drug-induced
- Breed-associated
What are the 4 types of idiopathic IMPA?
- Type I: Idiopathic (50%)
- Type II: IMPA with infection remote from joint (25%)
- Type III: IMPA associated with GI disease (15%)
- Type IV: IMPA associated with neoplasia
What is the most common drug associated with drug-induced IMPA and what breed is overrepresented?
- Sulfonamide antibiotics
- Doberman Pinschers, large breeds
How is diagnosis of systemic lupus erythematosus (SLE) made?
Major clinical signs and positive ANA titer (greater than 1:40 or over 160)
Major signs:
- Skin lesions
- polyarthritis
- hemolytic anemia
- glomerulonephritis or substantial proteinuria
- polymyositis
- leukopenia
- thrombocytopenia
What treatment of SLE seems to have the highest rate of remission?
Prednisone and levamisole (better) or cyclophosphamide
List 2 forms of breed associated IMPA
Shar-Pei fever
- familial amyloidosis
- Episodes of acute joint swelling and synovitis
- Poor prognosis with amyloid-induced renal failure
Japanese Akita IMPA
- May be associated with aspetic meningitis
How is rheumatoid arthritis diagnosed?
When 7 of the criteria are satisfied
- With 1-5, joint signs should be present for at least 6 weeks
- 2 criteria of 7, 8, and 10 should be satisfied
Is elevated rheumatoid factor specific for rheumatoid arthritis?
No - May be elevated in many chronic inflammatory diseases
What are other forms of erosive polyarthropathy (other than rheumatoid)
- Polyarthritis of Greyhounds
- Feline, chronic progressive polyarthritis
What surgical options are there for IMPA if non-responsive to medical management?
- Arthrodesis
- Excision arthroplasty
- Joint replacement
- Synovectomy
What are the most common bacteria in infective arthritis?
Dogs
- Staph intermedius
- Staph aureus
- B-haemolytic Strep
Cats
- Pasteurella multocida
- Bacteroides species
What are the main routes of bacterial invasion for infective arthritis?
- Hematogenous
- Direct penetration
- Local spread from adjacent tissue
List treatment options for bacterial infective arthritis
- Systemic antibiotics ( at least 28 days, repeat arthrocentesis prior to discontinuing)
- Joint irrigation
- Arthroscopic synovectomy
- Open exploratory arthrotomy
- Local Antibiotic delivery systems
What are some other pathogens which can cause an infective arthritis?
- Borrelia burgdorferi (ixodes ticks)
- Bacterial L-forms (cell wall deficient bacteria which can revert to their parent cell wall state in culture). Nocardia asteroides
- Mycoplasma
- Protozoal (leishmania, zoonotic, phlebotomine sand flies)
- Fungal (Coccidioides immitis, Crytpococcus neoformans, Blastomyces dermatitidis, Pororthrix shenkii, Aspergillus fumigatus)
- Rickettsial (Ixodes tick, Rickettsia, anaplasma, Ehrlichia)
- Mycobacterial (zoonotic, Tx controversial)
N3 and N6 fatty acids compete for incorporation into phospholipids and as substrates. What do higher concentrations of each cause?
High N6 = inflammatory
High N3 = anti-inflammatory
PUFA - polyunsaturated fatty acids are what?
Part of the cell membrane
precursors to eicosanoid hormones that regulate inflammation
Linoleic
Alpha-linoleic
arachidonic
EPA / DHA
Name five other analgesics for OA (other than NSAIDs):
Amantadine
Gabapentin
Acetaminophen
Codeine
Corticosteroids
What can phenylbutazone cause that is bad?
Blood dyscrasias
What is the precursor of all prostaglandins and thromboxanes?
PGH2
COX-1 called the constituative form because it is important for normal function in what cell types?
GI cells
platelets
endothelial cells
renal cells
COX-2 is called the inducible form because it is dramatically upregulated in inflammation. Where is it also constituative?
kidney
brain
GI mucosa protection (but not as much as cox-1)
What are the (7) radiographic features of OA?
Osteophytosis
Enthesiophytosis
Effusion
Soft tissue swelling
Subchondral sclerosis
Intraarticular mineralization
Subchondral cysts
