Ch 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
Whar percentage of adult animals have OA?
- 60% adult cats
- 20% adult dogs
What factors contribute to an individuals susceptibility to OA?
- Genetics
- Age
- Systemic factors (eg obesity)
What genes have been shown to be associated with early onset arthritis in people?
- Point mutations in type II collagen
- Mutations in genes encoding types IV, V and VI collagen
- Cartilage oligomeric matrix protein (COMP)
- Polymorphisms in the prostaglandin endoperoxidase synthase-2 (PTGS-2) which encodes COX-2 enzyme
How do chondrocytes change as they age?
- Synthesise smalled, 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 diminshed
- MMPs and aggrecanases cause c-terminal truncation
- Shorter molecules contain fewer chondroitin sulphate side chains but greater quantities of ketatin sulphate
- Therefore, have less ability in imbibe water reducing the compressive stiffness
How does obesity predispose to the formation of OA?
- Increased load on the joints
- Alters joint alignment
- 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 degredation of articular cartilage
What are the three overlapping phased of articular cartilage changes with OA?
- In beginning, extracellular matrix degrades on a molecular level, water content increased, size of aggregan molecules decreased and structure of collagen network is damaged leading to reduced stiffness
- Second, chondrocytes try to compensate through enhanced proliferation and metabolic activity. Cell clusters appear surrounded by newly synthesised matrix molecules.
- Finally, chondrocytes are no longer able to keep up, resulting in conplete loss of cartilage tissue
Imbalance between anabolic and catabolic processes. Initially there is an increase in cartilage thickness and swelling
What inflammatory cytokines are known to upregulate the synthesis of 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 aggercan and Type II collagen
- Upregulation of MMP-13, disintegrin and ADAMTS-5
- Downregulation of MMP-1
What role does 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 stimulare aggrecan and collagen synthesis?
- IGF-1
- IGF-2
- TGF-b
What is the synovium?
A discontinuous layer of fibroblast-like and macrophage-like cells
What cell is a key cell in driving synovial control of cartilage metabolism?
Macrophages (through release of catabolic cytokines IL-1b and TNFa)
What are the precursors of osteophyte formation?
Mesenchymal stem cells in periosteum ot synovial lining
What fibres 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 even noxious stimuli of the normal joint but begin to respond to mechanical stimuli during inflammation
What enzyme plays a role in central sensitisation?
COX enzymes
What imaging methos 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?
What receptor does paracetamol act on?
Indirect activation of cannabinoid (CBI) receptors by conjugating with arachidonic acid to produce an endogenous cannabinoid (N-arachidonylphenolamine)
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 and their COX1:COX2 ratio
Carprofen
- Propionic acid derivative
- COX ratio 17 (COX-2 selective)
Deracoxib
- Coxib class
Etodolac
- indole acetic acid derivative
- mixed COX 1 and 2
- Can cause KCS
Firocoxib
- pyridylsulphone
- COX-2 specific, ratio 342-430
Ketoprofen
- Propionic acid
- COX-1 selective
Mavacoxib
- Preferential COX-2, ratio 21
- Therapeutic conc maintained for 30 days (80d in 5%)
Meloxicam
- oxicam group
- COX-2 selective, ratio 3
- Only one licensed in cats
Phenylbutazone
- Slightly COX-2 selective, ratio 2.64
Robenacoxib
- coxib class
- Highly COX-2 selective, ratio 140
- Persists longer at site on inflammation
Tepoxalin
- Non-selective COX inhibitor and inhibits 5-lipoxygenase
- 10% GI adverse event
- Ameliorates collagen degradation in vitro
Tolfenamin 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
What is the action of IM polysulphated glycosaminoglycan?
- Inhibits cartilage oligomeric matrix protein degradation
- May also maintain chondrocyte viability or stimilate chondrocyte division
What are the actions of pentosan polysulphate?
- 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 a-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 are considered key mediators of inflammation in OA?
PGE2 and LTB4 (leucotriene B4)
What is the most effective of the n-3 FAs?
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
What is a significant genetic risk factor for ANA-positive IMPA?
DLA (dog leucocyle 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 ABx
- Doberman Pinschers
How is diagnosis of SLE made?
Major clinical signs and positive ANA titer (greater than 1:40 or over 160)
Major signs:
- Skin lesions
- polyarthritis
- haemolytic anaemia
- glomerulonephritis or substantial proteinuria
- polymyositis
- leukopaenia
- thrombocytopaenia
What treatment of SLE seems to have the highest rate of remission?
Prednisone and levamisole
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 following criteria are satisified
- 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 rheumatoud 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?
- Haematogenous
- 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 ABx delivery systems
What are some other pathogens which can cause an infective arthritis?
- Borrelia burgdorferi (ixodes ticks)
- Bacterial L-forms (cell wall deficient bacterial which can revert to their parent cell wall state in culture). Norcardia 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)
Is elevated rheumatoud factor specific for rheumatoid arthritis?
No - May be elevated in many chronic inflammatory diseases
