Ch 68 Arthritis Flashcards
type of arthritis
define OA
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
Define osteoarthritis
- Features of OA include cartilage degradation, bone remodelling, subchondral sclerosis, osteophyte formation, joint and synovial inflammation, and loss of normal joint function
- The loss of articular cartilage is considered its hallmark
- considered a “wear and tear” degenerative disease in the past > recognise the presence of an inflammatory state
What percentage of adult animals have OA?
60% adult cats
20% adult dogs
Aeitiology of OA
- multifactorial aetiology that results in a heterogenous phenotype.
- The specific pathways remain largely uncertain, though likely involve interrelated biological, mechanical, and structural pathways
- Current models: each individual has an inherent susceptibility + local factors at the joint level
What factors contribute to an individuals susceptibility to OA? (3)
Genetics
Age
Systemic factors (eg obesity)
What factors contribute to joint biomechanics in OA? (4)
Injury
developmental abnormality
instability
overload
What genes have been shown to be associated with early onset arthritis in people?
genes
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?
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?
age
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?
systemic
- Increased load on the joints
- Alters joint alignment
- Causes a systemis 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
Body weight at 5 years of age correlated moderately with severity of hip osteoarthritis, suggesting that body weight alone might not be the primary driving force for development of hip osteoarthriti
83% of control fed dogs had developed radiographic hip osteoarthritis, compared with 50% of the diet restriction group, which had a longer median life span.
evidence is compelling that optimal body condition score limits the appearance (and progression) of osteoarthritis in dogs.
gender/neuter status of OA
- Data on the effect of gender status on canine osteoarthritis are sparse
- gender did not show any significant effect on hip dysplasia
- boxers: neutered dogs were 1.5 times more likely to develop clinical hip dysplasia, compared with sexually intact dogs
- neutering in both males and females is associated with increased risk of ligament rupture
- elbow osteoarthritis, males were found to be at 1.8 times greater risk of developing osteoarthritis compared to females,187 but the effect of neutering on elbow osteoarthritis is not clear
nutrition, exercise, and housing conditions.
very few studies have explored the effects of environmental factors on the development or progression of canine osteoarthritis.
OA pathophysiology
- disease of joint metabolism involving a homeostatic imbalance between maintenance and degradation.
- a failure of the whole joint rather than just the articular cartilage
- The synovial joint is an organ with cross-talk between cartilage, synovium, bone, ligament and synovial fluid
- The exact mechanisms and pathways remains unclear
- Pro-inflammatory cytokines, reactive oxygen species (ROS), nitric oxide, matrix degrading enzymes and biomechanical stress are major factors responsible for the progression of OA in synovial joints.
Several proinflammatory mediators such as interleukins (Il-1, IL-17), tumour necrosis
factor (TNFα) produced by synovial cells and chondrocytes upregulate proteolytic enzymes MMP
by chondrocytes. Leading to cartilage and ECM breakdown and a perpetual pro-inflammatory
cycle
pathophysiologic process of osteoarthritis can be divided into three overlapping stages
1.extracellular matrix degrades on a molecular level,
- water content increased,
- size of aggregan molecules decreased
- structure of collagen network is damaged > reduced stiffness
2.chondrocytes try to compensate
- enhanced proliferation and metabolic activity.
- Cell clusters > newly synthesised matrix molecules.
3.chondrocytes can’t keep up,
- resulting in complete loss of cartilage tissue
- Imbalance between anabolic and catabolic processes.
- Initially > increase in cartilage thickness and swelling
cartilage
- specialized connective tissue consisting of chondrocytes and extracellular matrix (ECM), composed of type-II collagen and aggrecan
Chondrocytes
- in repsonse to inflammatory stimuli > produce proteinases (MMP), PG, NO + arachidonic cascade
- Chronic mechanical stresses > express degenerative enzymes
via mechanoreceptors, leading to the destruction of cells and the collagen ECM
cartilage
What inflammatory cytokines are known to upregulate the synthesis of MMPs and other proteolytic enzymes by chondrocytes? (4)
IL-1
IL-17
IL-18
TNF-a
Synthesis of tissue inhibitors of metalloproteinases (TIMPS) are concomitantly decreased
Chondrocytes express in repsonse to inflammatory stimuli
- proteinases (MMP),
- PG,
- NO
arachadonic cascade
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 is the synovium?
role in OA?
- A discontinuous layer of fibroblast-like and macrophage-like cells
- a critical provider of synovial fluid lubricant components and articular cartilage nutrients and is therefore vital for joint homeostasis
OA: involved early in the process, unclear whether inflammation occurs first or in response to cartilage degradation
What cell is a key cell in driving synovial control of cartilage metabolism?
Macrophages (through release of catabolic cytokines IL-1b and TNFa)
synovial cells produce what mediators that upregulate MMPs?
Catabolic and proinflammatory mediators:
- IL-6,
- IL-8,
- IL-17
- TNFα,
- nitric oxide,
- prostaglandin E2
- neuropeptides
leads to degradation of cartilage ECM
> perpetuates a proinflammatory environment, where cytokine production by synovial cells and chondrocytes are stimulated in a continuous cycle
Subchondral bone
- Bone morphogenic proteins and TGFß may be upregulated and
contribute to the formation of osteophytes - subchondral sclerosis
contributes to accelerate OA via increasing mechanical stress on overlying articular cartilage - Whether subchondral changes are a cause or a result of cartilage degradation is still a subject for debate
Innes 2017 OA summary
- articular cartilage: ECM degradation, increased water content, decreased aggrecan size
→ loss of collagen network structure → chondrocyte proliferation
→ ultimate failure of reparative efforts
- pro-inflammatory cytokines: IL-1, IL-17, IL-18, TNF-α
- increase MMP/proteolytic enzyme synthesis
- reduce tissue inhibitors of metalloproteinases (TIMPS)
- iNOS → NO → inhibition of chondrocyte matrix synthesis, MMP activation
chondrocyte apoptosis
- reactive oxygen species → chondrocyte apoptosis
- COX-2 → PGE2 → decreased proteoglycan synthesis, increased aggrecan and type II collagen degradation
- reduction in insulin-like growth factor (IGF) and TGF- β- synovium – synovial macrophages → release of IL-1β, TNF-α → degradation of cartilage
- important in OA-related pain
- subchondral bone – TGF-β → osteophyte formation
- pain – inflammatory mediators → sensitisation of primary afferent nociceptors
- central sensitisation – COX, NO-induced apoptosis
- synovium – synovial macrophages → release of IL-1β, TNF-α → degradation of cartilage
Abnormal joint metabolism
- Under stressed conditions, chondrocytes and synoviocytes adapt their metabolism by shifting from one metabolic pathway to another.
Metabolic alterations include
- mitochondrial dysfunction,
- enhanced anaerobic glycolysis
- altered lipid and amino acid metabolism
TRPV1 is expressed in
osteoarthritic joints, playing a role in the development of inflammatory
and chronic pain
Pain in Osteoarthritis
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 noxious stimuli of the normal joint > respond to mechanical stimuli during inflammation
sensitization of primary afferent fibers for mechanical stimuli by inflammatory mediators
- TNF-α,
- IL-6,
- bradykinin,
- PGE2,
- substance P
play a significant role in adapting the responses of nociceptors within the articular tissues.
joint pain results in the development of central sensitization, what enzyme plays a role?
COX enzymes
COX inhibitors can prevent central sensitization
imaging of OA
- rads provide only information on bony changes such as osteophytosis and sclerosis
- value of osteophytosis for staging OA severity is controversial
- MRI: canine cartilage is so thin, most MRI do not have sufficient signal-to-noise ratio to allow accurate delineation - MRI can provide info on structures such as menisci, ligaments, and tendons
- CT highly sensitive to the detection of osteophytosis
- Scintigraphy using technetium99m linked to a diphosphonate carrier> provide information on bone remodeling. The diphosphonate binds to hydroxyapatite crystals, and recently formed bone has large crystals for the carrier to bind.
- Arthroscopy is minimally invasive, quick and effective method to assess articular pathology. Consider if performing diagnostic scope will change course of disease….
What are the expected cell counts and differential counts of normal synovial fluid, OA, rheumatoid, Nonerosive IMPA and Infective arthritis?
conservative mgmt of OA
list symptom modifying
list sturcture modifying
- weightloss (Some evidence, client education, nutritional, exercise, weihtloss drugs)
- exercise
- medical (symptom- or structure-modifying agents)
symptom
- nsaid
- paracetamol
- amantadine
- gabapentin
- codiene
- grapipant
- synovetin
- bedinvetmab
structural
- Pentosan polysulfate
paracetamol
10 to 15 mg/kg orally every 8 or 12 hours
- Paracetamol is a centrally acting analgesic
- promote GABA and glutamate release
- nti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the central nervous system
- weak agonist of cannabinoid receptors
- potent activator of TRPV1 receptor (modulates nociception in neurons)
not licenced
Codeine
metabolized in vivo to the primary active compounds morphine and codeine-6-glucuronide.
grapiprant
clinical efficacy for long-term tx of OA unknown
- selective inhibition of PGE2-EP4 receptor
gabapentin
evidence lacking, 1 study suggesting some improvement
amantadine
N-methyl-D-aspartate (NMDA) receptor antagonist
- 1 study suggest benefit
tramadol
mixed reports, may be insufficient as sole analgesic but may be beneficial
used together with other analgesics
corticosteroids
minimal trials, single study suggesting improvement with IA injection
anti-inflam and immunosuppressive → reduced superoxide, MMP, PG
- reduced inflammation of synovium → reduced effusion, increased endogenous hyaluronic acid
- may be chondrotoxic → use in terminal OA with marked cartilage wear
- possible systemic effects in cases with marked synovitis
Corticosteroids, such as glucocorticoids, inhibit the arachidonic acid pathway by decreasing the release of arachidonic acid from cell membranes
> production of lipocortin, a phospholipase α2 inhibitor
How frequently can intraarticular steroid injections be performed?
One injection every 6 weeks with no more than 3-4 per year
synovetin
radionucleotides → reduce synovial hypertrophy → reduced pain, inflammation
- tin-117m
particles phagocytosed by synovial macrophages and synonviocytes → elimination of inflamed synoviocytes by focal irradiation
→ treatment success >70% at all time points (90d intervals for 1y)
- reduced pain, lameness and improved functionality
- clinically effective for up to 1 year in 50% cases (44 dogs)
bedinvetmab
- monoclonal antibody (mAb) that targets nerve growth factor (NGF)
- The goal of using Librela is to reduce excessive NGF and thereby reduce pain.
NGF pain pathway
-modulation of nociceptive activity > NGF increased in dogs with OA
- produced/released in response to noxious stimuli
→ binds to NGF-receptors:
- NGF-TrkA internalised, transported to sensory neuron cell body at dorsal
root ganglia → modulates expression of nociceptive receptors
→ increase in excitability of primary afferent fibres
→ increase in pro-nociceptive neurotransmitters (substance P, CGRP)
significant improvement in pain interference, pain severity and QOL components of CBPI
- no treatment specific side-effects
- improved CBPI scores vs placebo
rapidly progressive OA (RPOA) seen in human studies with concurrent use of anti-NGF mABs and NSAIDs
List some licensed NSAIDs, their class and their COX1:COX2 ratio
Carprofen
- Propionic acid derivative
- COX ratio 17 (COX-2 selective)
Firocoxib (Previcox)
- pyridylsulphone
- COX-2 specific, ratio 342-430
Mavacoxib (trocoxil)
- 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
Robenacoxib (onsior)
- 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
nsaid
- drugs that inhibit one or more steps in the metabolism of the arachidonic acid cascade
- systematic review of management of canine osteoarthritis concluded that evidence was strongest for the efficacy
- Pye 2022: provide analgesia for OA pain, none shown to be superior
nsaid Cyclooxygenase (COX) inhibition
Phospholipids are released from the cell membrane when cell damage occurs.
- arachidonic acid (PUFA), is produced by the action of phospholipase A2 on cell membrane phospholipid
- COX pathway generates PGH2, the precursor of all prostaglandins and thromboxanes + release of toxic oxygen free radicals
- PGE2 = predominant eicosanoid associated with inflammatory conditions (vasodilation, increased vascular permeability, decreases the nociceptive threshold thereby enhancing pain)
- decrease PGE2 formation is viewed as a desirable event in decreasing pain
- isoforms: COX-1 constitutive form produces PGs important for normal physiologic function, produced by GIT cells, platelets, endothelial cells, and renal cells. COX-2 inducible form is tightly controlled under basal conditions, but is dramatically upregulated in the presence of inflammation
- nonsteroidal antiinflammatory drugs have their major action by blocking prostaglandin synthesis, by binding to and inhibiting COX
- COX-2 is constitutively expressed in the kidney and brain and mediates a cytoprotective effect in damaged or inflamed gastrointestinal mucosa. No clear delineation is noted between beneficial and inflammatory prostaglandins
TNF and IL-1 stimulate the expression of COX-2
- synovial and subchondral bone tissue from canine hips with osteoarthritis have increased COX-2 expression compared to healthy controls
COX-1:COX-2
- hypothesis selectively inhibits COX-2 without affecting COX-1 will allow analgesia without the common side effects of COX-1 inhibition
- amount of drug necessary to inhibit 50% of activity of each enzyme is recorded and expressed as a ratio of COX-1:COX-2
- drug that inhibits COX-2 at a lower concentration than the concentration necessary to inhibit COX-1 is probably safer
- Care is required to not overinterpret these ratios between drugs/studies and due to species differences
Lipoxygenase (LOX) inhibition
- lipoxygenases on arachidonic acid > (5-HPETE), an intermediary > leukotrienes
- LTB4 is a potent chemotactic agent that attracts neutrophils and inflammatory cells
- LTC4, LTD4, and LTE4 are more direct proinflammatory compounds
- ## potential sequel of cyclooxygenase blockade is increased production of leukotrienes > partially explain the less than complete relief provided by nsaid
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.
- SE: inappetence, V+ an D+
- true incidence of gastrointestinal toxicity in dogs unknown
- Risk factors: decreased albumin levels, decreased hepatic and renal function
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)
- PGE2 and PGI2 (COX-1 and COX-2) have important roles in maintaining renal blood flow > cardiac, renal, or liver disease in geriatric patients; hypovolemic states
long term study of nsaid use
- when limiting the analysis to placebo-controlled, blinded studies, there was no significant difference in the incidence of adverse events between treated and control dogs
- longer-term use supported with lo risk of adverse events
- vomiting and diarrhoea most common + other GI-associated clinical signs
- hepatotoxicity more likely idiosyncratic reaction to specific drug
- renal effects → no difference among NSAIDS or vs control
- no significant effect on bleeding disorders
owner assessed pain questionaires
CBPI, COI and LOAD sufficient evidence to support validity and internal consistency
FMPI → reliable, refined to improve responsiveness
nsaid shown to alter the inflammatory response by inhibiting activation of neutrophils
Pye 2022 – review of pharmaceutical treatments
structure-modifying drugs – limited evidence for various neutraceuticals
- some support for pentosan polysulphate and polysulphated glycosaminoglycan
- mesenchymal stem cells – generally show beneficial outcomes
- clinical trials generally small sample size with mostly subjective outcomes
measures
- platelet-rich plasma – studies report improvement but small sample sizes and variation
in methodology and lack of controls
high strength of evidence for carprofen, firocoxib and meloxicam
What are the actions of pentosan polysulphate?
semisynthetic glycosaminoglycan
- 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
Pye 2022: some support for pentosan polysulphate (clinical trials mixed results)
Barbeau-Gregoire 2022 – review/meta-analysis of enriched diets and neutraceuticals
- clinical analgesic effect with omega-3-enriched diets, omega-3 supplements, cannabidiol
- weak efficacy of collagen
- very marked non-effect of chondroitin glucosamine neutraceuticals
chondroitin and glucosamine
- current evidence is insufficient to recommend the use of chondroitin sulfate for the management of canine or feline osteoarthritis
- Clinical trials of glucosamine alone in veterinary species are lacking
Essential fatty acids
- polyunsaturated fatty acids— contain more than one carbon-carbon double bond within their structure.
- linoleic acid and linolenic acid (essential fatty acids)
- arachadonic acid ( n-6 fatty acid) and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), n-3 fatty acids, may be derived from diet
- n-3 and n-6 fatty acids compete for incorporation into phospholipids and as substrates for COX-1 and COX-2
- higher proportions of n-6 fatty acid within cell membranes are believed to promote the production of inflammatory prostaglandins, leukotrienes, and thromboxanes.
- Studies in dogs have shown that essential fatty acids (derived from fish oils) in a functional food were able to influence synovial fluid matrix metalloproteinase. Clinical studied also show improvments compared to controls
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
Mesenchymal Stem Cell
- aims to develop biologic, cell-based therapies to repair or replace injured or eroded tissues such as cartilage.
- autologous adipose tissue and extraction of stromal cells.
- moderate evidence that intra-articular allogenic stem cell therapy has some efficacy for
reducing pain and lameness vs placebo
- not compared to other therapeutics - generally favourable outcomes but limited clinical evidence
Kim 2019 – treatment success for intra-articular (elbow) MSC higher than placebo based on CBPI
and pVF
surgical mgmt
- joint replacement
- arthrodesis
etiopathogenesis of immune-mediated polyarthritis
human
- remian unclear
- data suggest that the disease involves abnormal B-cell–T-cell interaction
- immune complexes as the initiators, even if not the sole perpetuators, of inflammation.
- Persistence of the antigenic stimulus and phagocytosis of immune complexes vs derangement of normal downregulation of the immune system > chronic form
- inciting antigen can be identified in some forms, most remain idiopathic
- Extra-articular manifestations: often a consequence of immune complex deposition (glomerulonephritis) or autoantibody formation (IMT)
What is a significant genetic risk factor for ANA-positive IMPA?
DLA (dog leucocyle antigen) class II haplotypes
hx
- multiple joint pain or swelling, generalized stiffness, shifting lameness, or pyrexia of unknown origin
- any age in any breed or sex of dog or cat
- sometimes will affect only a single joint
What is the best medium for a culture of synovial fluid?
Blood culture bottle
What will a synovial biopsy show with IMPA?
if not enough SF fluid
Infiltration of B- and T-lymphocytes, macrophages and neutrophils
Dx
- cytology from a minimum of three joints > recommended to sample 4
- often preferentially targets smaller joints, particularly the carpus and tarsus
- total and differential cell counts (to differentiate bewteen
- culture if unsure
- categorize the type> evaluation of other body systems (bloods, imaging of chest, abdo and heart)
rads of joints
- initial results are usually uninformative and proabbly not needed
- monitor for erosions, periosteal reactions, subluxations, and deformities.
Hematology, Serum Biochemistry, and Urinalysis
- anemia, leukocytosis or leukopenia, neutrophilia with a left shift, and thrombocytopenia
- urea, creatinine, alkaline phosphatase, alanine transferase
- decreased serum albumin concentrations (PLE or PLN)
ANA
- Antinuclear antibodies
- support diagnosis of systemic lupus erythematosus
What are the main types of nonerosive IMPA? (5)
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%)
- most dogs responded to initial immunosuppressive treatment
- 31% of dogs relapsed, required further treatment, or both.
Type II: IMPA with infection remote from joint (25%)
- endocarditis, respiratory infection, genitourinary tract infection, pyoderma, and abscessation
- treatment of the initiating infection can bring about resolution > chronic may persist
Type III: IMPA associated with GI disease (15%)
Type IV: IMPA associated with neoplasia
- surgical removal/medical treatment of tumor usually results in marked regression
What is the most common drug associated with drug-induced IMPA and what breed is overrepresented?
Sulfonamide ABx
Doberman Pinschers
- immune complex hypersensitivity reactions occur as a result of drug-antibody interactions
- withdrawal of the drug results in improvement within 1 to 3 days
- multisystemic disease may be apparent
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
rheumatoid arthritis
radiographically diagnosed erosive changes in joints and the appearance of rheumatoid factor in serum
Is elevated rheumatoud factor specific for rheumatoid arthritis?
No - May be elevated in many chronic inflammatory diseases
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
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 (carpal and tarsal arthrodesis)
Excision arthroplasty
Joint replacement
Synovectomy
Treatment of Immune-Mediated Polyarthritis
- elimination of the inciting cause if this can be identified
- immunosuppressive doses (2 to 4 mg/kg) of prednisolone.
- Refractory cases, cases showing marked corticosteroid-related side effects need disease mdoyfing drugs
- cyclophosphamide or azathioprine, cyclosporine
- may result in remission in 1 to 4 weeks, and the drugs then are usually continued for an additional 1 to 3 months before gradual withdrawal
Prognosis for Canine and Feline Immune-Mediated Polyarthritis
- most dogs with type I immune-mediated polyarthritis responded to initial immunosuppressive treatment, but approximately one-third relapsed, required further treatment, or both
- canine rheumatoid arthritis appears to be challenging, and the prognosis appears guarded
What are the most common bacteria in infective arthritis?
Dogs
- Staph intermedius
- Staph aureus
- B-haemolytic Strep
Cats
- Pasteurella multocida
- Bacteroides species
- oral flora
dx sepetic arthritis
- neutrophils may show degenerative and toxic changes
- cell count greater than 50 × 109 cells/L and greater than 40% neutrophils
- bacteriologic culture: many are negative
- PCR? (possible false-positive results)
What are the main routes of bacterial invasion for infective arthritis?
usually monoarthopathy
Haematogenous
Direct penetration
Local sread from adjacent tissue
stifle, elbow, and carpus most common
Risk factors for bacterial infective arthritis
- previous surgery to the joint
- preexisting joint disease (e.g., osteoarthritis).
hypothesized that increased vasculature and blood flow to arthritic joints contribute to increased frequency of bacterial invasion
0% and 2.7% joint infection rate post-sx
List treatment options for bacterial infective arthritis (3)
Systemic antibiotics
- at least 28 days
- repeat arthrocentesis prior to discontinuing
- broad-spectrum antibiotics are used pending C&S (Clav, Ceph + metronidazole)
Joint irrigation/arthroscopy
- contraversial > no convincing evidence suggests that surgical intervention is necessary, unless gross contamination of the joint is evident or if appropriate antibiotic therapy fails
- Arthroscopic inspection and lavage of the joint
- Arthroscopic synovectomy
- Open exploratory arthrotomy
Local ABx delivery systems
- PMMA (no biodegradable)
- biodegradable > inorganic salts like hydroxyapatite or collagen
evidence base for the correct approach to canine and feline patients with bacterial infective arthritis is currently small and consists of retrospective case series
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)
degree of articular cartilage damage caused by bacterial infection
depends on the
- number, type, and virulence of the organism present;
- extent to which the organisms multiply;
- local and general immunity of the patient.
mediated by
- Proteolytic enzymes such as matrix metalloproteinases
- inflammatory cytokines such as TNF-α and IL-1 released by macrophage and synoviocytes
Patient Monitoring and Prognosis
acute > response in 24-48hr, reduction in pain and lameness should be apparent, along with resolution of pyrexia
- repeat centesis 7 to 14 days of therapy
- antibiotic therapy until the cell count is within the normal (,3% Neutrophils)
- 17 of 32 joints recovered fully and 13 partially, and 2 failed to recover
- often have preexisting pathology (e.g., osteoarthritis), and so a full recovery is unrealistic.
Retrospective analysis describes safety
of therapeutic joint injections in dogs
Miller 2023
Therapeutic joint injections in dogs are safe, with an extremely low risk of major adverse effects. Transient soreness is a commonly expected minor adverse event. The use of stem cells or larger injectate volumes (confined to the stifle and smaller distal joints) may be more likely to invoke discomfort
Description and outcome of dogs
with primary immune-mediated
polyarthritis: 73 cases (2012-2017)
S. Ravicini 2023
Ninety-five percent (69/73) of dogs responded favourably
81% of dogs had a well-managed
disease for an extended timeframe (≥1131 days)
death in 19% (14/73)
Relapse in 53% (39/73) dogs
Complete cureachieved in (63%).
60% corticosteroids alone achieved a
complete cure
Advances in the pharmaceutical treatment options for canine osteoarthritis
C. Pye 2022
review of pharmaceutical treatments
- NSAIDs – provide analgesia for OA pain, none shown to be superior
- grapiprant – clinical efficacy for long-term tx of OA unknown
- selective inhibition of PGE2-EP4 receptor
- paracetamol – no published data on canine OA specifically
- peripheral and central COX inhibition + anti-nociceptive central effect on serotonergic pathways, endocannabinoid system, L arginine/NO pathway
- NGF monoclonal antibodies – initial evidence promising for alleviation of pain in OA
- tramadol – mixed reports, may be insufficient as sole analgesic but may be beneficial used together with other analgesics
- gabapentin – evidence lacking, 1 study suggesting some improvement
- NMDA-receptor antagonists – 1 study suggests benefit as adjunct analgesic
- cannabidiol (CBD-oil) – mixed results, limited evidence
- corticosteroids – minimal trials, single study suggesting improvement with IA injection
- structure-modifying drugs – limited evidence for various neutraceuticals
- some support for pentosan polysulphate and polysulphated glycosaminoglycan
- mesenchymal stem cells – generally show beneficial outcomes
- clinical trials generally small sample size with mostly subjective outcomes
- platelet-rich plasma – studies report improvement but small sample sizes and variation in methodology and lack of controls
- anti-inflammatory cytokine plasmid DNA therapy
Clinical effectiveness and safety of intraarticular
administration of a 117mTin radiocolloid (SynovetinOATM) for
treatment of early and intermediate grade osteoarthritis of the
elbow in a dose finding study conducted in 44 dogs
Lattimer 2023
positive response to treatment with all doses based on CBPI
- 64.75 Mbq dose (medium) → highest and most durable response at 9m
- response not universal
- clinically effective for up to 1 year in 50% cases
- radiation safety – very short-range conversion electrons and 99% maintained in joint
4CYTE™ Epiitalis® Forte
evaluation consisted of an objective lameness
assessment (TPI%[total pressure index]) using a gait analysis
(GAITRite® Portable Walkway System) and a subjective qualityof-
life questionnaire, the Helsinki Chronic Pain Index (HCPI).
74% (34/46) registered a numerical improvement in TPI%
in their worse limb. In addition, of the 93.5% of the dogs that
demonstrated improvement in their HCPI scores by at least 5%
on the quality-of-life questionnaire,
A randomised controlled masked clinical trial of two treatments
for osteoarthritis in dogs
T Whittem 2021
AVJ
4Cyte non-inferior to carprofen at d14 and d28
Feline non-erosive immune-mediated
polyarthritis: a multicentre, retrospective
study of 20 cases (2009–2020)
Florence Wootton
Prognosis for feline IMPA can be good. Multimodal immunosuppression was often
required. IMPA should be considered in lame cats, with or without pyrexia, when there is no evidence of trauma or
infection. The tarsal joints should be included in the multiple joints chosen for sampling. Ligament laxity can occur
in non-erosive feline IMPA.
Autologous point-of-care stromal vascular fraction transplantation
in dogs with advanced osteoarthritis of the knee and hip joints
M Schroers 2024
AVJ
10 g of falciform
fat
in-house preparation
of the SVF
showed improvement up to a maximum of 3 months after surgery
only a short-term effect
can be expected, which calls into question the effort and costs
involved.
Current evidence for non-pharmaceutical,
non-surgical treatments of canine osteoarthritis
C. Pye 2024
- Weight management has shown to be beneficial
- evidence for the use of nutraceuticals such as omega-3 fatty acids (greater PVF values and QOL scores)
- green-lipped mussel and elk velvet antler demonstrate promising results (clarify the optimal dose)
- Acupuncture require more research
- lack of randomised controlled trials investigating the efficacy of different physiotherapy programmes
assessment of the above therapies compared to pharmaceutical therapies alone would be useful to determine
their efficacy in reducing clinical signs of canine OA.
Owner evaluation of quality of life
and mobility in osteoarthritic cats
treated with amantadine or placebo
Shipley 2020
Amantadine significantly decreased activity, but improved owner-identified impaired
mobility and owner-perceived quality of life in cats with osteoarthritis. Amantadine appears to be an option for the
symptomatic treatment of osteoarthritis in cats
Evaluation of a Single Intra-Articular Injection of
Autologous Adipose Tissue for the Treatment of
Osteoarthritis: A Prospective Clinical Study in Dogs
Greta S. Pavarotti 2020
to provide ‘minimally manipulated’ adipose tissue
- no change to radiographic scores from d0 to d180
- delayed progression?
- reduced lameness and CBPI scores at all time points
- gradual improvement in VI, pVF and %bWt distribution up to d180
Influence of clipping on bacterial contamination of canine
arthrocentesis sites before and after skin preparation
Lavallée 2020
Randomized controlled trial.
Study population: Thirteen shorthaired beagle-cross dogs.
Aseptic skin preparation:4% chlorhexidine followed by 70% isopropyl alcohol.
Aseptic skin
preparation reduced bacterial CFU in both groups.
In this study we did not find evidence to support that
clipping of canine arthrocentesis sites is required for effective aseptic skin
preparation. A prospective clinical trial is required
Ligament Laxity in Nonerosive Immune-Mediated
Polyarthritis in Dogs: Five Cases (2009–2017
Retrospective evaluation of 103 cases of septic arthritis in dogs
Phillips 2022
vet record
spontaneous septic arthritis common
- stifle (40%) and elbow (24%) most commonly affected
- 63% had pre-existing OA – associated with recurrence
- outcome: successful outcome associated with early tx, septic arthritis due to direct
penetration
- successful outcome achieved regardless of treatment type
- recurrence associated with pre-existing OA and higher bWt
Spontaneous Septic Arthritis of Canine Elbows: Twenty-One Cases
Mielke 2018
spontanous septic arthritis
- prior ortho sx 11/21, 3 distant from elbow but 2/3 within 2m of elbow sepsis
- pre-existing OA in 14/15 cases, 12/21 culture positive, 29% pyrexic
- antibiotic therapy alone → 94% resolution
