University of Edinburgh



Osteoarthritis in brief Part 1 – aetiology, pathogenesis, pain and diagnosisSummaryOsteoarthritis is a debilitating condition affecting up to 20% of canine and 60% feline patients. Whilst diagnosis is fairly straightforward, the aetiology behind the disease process and therefore the treatment strategies are not. Multimodal management is the mainstay of controlling clinical signs and ensuring patient comfort, however this involves potentially long-term pharmacologic and dietary control and requires significant client compliance.Research into disease pathogenesis and treatment strategies is ongoing but evidence, especially relating to many therapies and nutritional supplements is currently lacking. Genetic research continues as does that into mesenchymal stem cell therapy and cartilage repair and regeneration but clinical “cure” remains a distant objective. This series of two articles aims to briefly cover the basic concepts relating to OA and its management and some new treatment strategies will be discussed.The hope is that by presenting the basic facts and concepts, the reader will be able to build on this knowledge and approach the case of the osteoarthritic animal in a well-considered manner.IntroductionOsteoarthritis (OA), also termed degenerative arthritis, degenerative joint disease or osteoarthrosis, refers to a degenerative condition of the synovial joint caused by complex biological and biochemical interactions and characterised by articular cartilage degeneration and inappropriate repair, osteophyte formation and subchondral bone remodelling, synovial membrane inflammation, periarticular tissue pathology and low-grade inflammation within the joint itself. It is a complex condition, without a single aetiology and the cause is usually multifactorial. The condition is irreversible and often results in end-stage joint disease. Approximately 20% of adult dogs are affected at any one time (Johnston, 1997), usually secondarily to structural, functional or traumatic joint abnormality. Common orthopaedic conditions including cranial cruciate ligament disease and hip dysplasia will inevitably lead to the development of OA, as will developmental diseases including avascular necrosis of the femoral head and osteochondritis dissecans (Renberg, 2005). In cats the condition is slightly different with up to 60% cats in one study reported to have radiographic evidence of OA in the appendicular skeleton, despite no obvious initiating cause being identified (Hardie, 2002).Aetiology and PathogenesisIn a model of canine and feline osteoarthritis (Innes, 2012) a predisposition to osteoarthritis and joint biomechanics combine to initiate the inflammatory biochemical pathways that cause the pain and disability associated with the condition. Genetics, age and systemic factors such as obesity are linked to the development of the condition, whilst environmental factors such as nutrition, exercise and housing conditions may all play a role in the progression of the disease. Socioeconomic factors and co-morbidities also play a role in the severity of the signs seen.Joint biomechanicsThe Normal Synovial JointThe synovial joint is an organ, comprising articular (hyaline) cartilage, subchondral bone, synovial fluid, synovium and ligaments. The function and health of the joint relies on all these components, and also on other structures and organs of the musculoskeletal system including bones, muscles and tendons. Hyaline cartilage of the normal joint provides a low-friction, weight-bearing surface that is relatively resistant to deformation during compression. The cartilage has high water content and a unique extracellular matrix containing collagen, proteoglycans and glycoproteins. The cartilage absorbs water from the synovial fluid during periods of inactivity and gradually loses water under conditions of prolonged weight bearing, improving joint lubrication.The joint capsule provides support to the joint with a thick, outer fibrous layer and surrounding connective tissue. The inner layer, or synovium, contains blood vessels and nerves, supplying nutrients to the joint and maintaining levels of synovial fluid for lubrication. In normal dogs the synovium is only a few cells thick, and the synovial fluid present is an ultrafiltrate of plasma.The articular cartilage interdigitates with subchondral bone at the osteochondral junction forming a stable attachment and allowing shear forces to be converted to compressive forces. The subchondral bone is arranged in a lattice that allows the force transmitted from the cartilage to be distributed more evenly. The Synovial Joint in the OA patientDuring the development of OA multiple changes occur within the synovial joint. Initially, cartilage metabolism and the cellular content of the articular cartilage and subchondral bone alters, osteophytes and enthesiophytes are formed and inflammation of the synovium occurs. In the longer term, altered use of the affected joint leads to changes in the surrounding tendons, ligaments and muscle and, in cases with long-standing disease, chronic pain may develop.Articular cartilage is the primary tissue involved in the development of OA (Renberg, 2005). Disruption of the normal articular cartilage surface leads to a cycle of biochemical events that eventually cause the degradation of other joint tissues. This disruption can arise due to either abnormal motion on normal articular cartilage, or normal motion on abnormal cartilage and leads to fibrillation of the superficial layer (Goldring & Goldring, 2010). The cartilage surface begins to roughen and fissures develop reducing its ability to transmit load. Fragments of cartilage that are lost from the surface are phagocytosed by the synovium leading to inflammatory synovitis, evidenced clinically by effusion and changes in the composition of synovial fluid during arthrocentesis (see later). Macrophages and synovial cells are stimulated to release collagenases and hydrolytic enzymes, further contributing to the cartilage damage. As fibrillation worsens, damage to the chondrocytes themselves occurs and proteoglycans are lost from the cartilage matrix. As the protective mechanisms present in the normal matrix become lost a cycle of disease begins with progressive damage to the cartilage during weight bearing (Sutton et al., 2009). Fissures deepen into areas of cartilage erosion, exposing the subchondral bone underneath (Figure 1). This subchondral bone eburnation is often visible grossly within the joint as an area of “polished” bone.The joint capsule becomes thick due to a combination of fibrin deposition and inflammatory oedema. Within the joint, villous hypertrophy of the synovium develops in response to the influx of inflammatory cells. Joint effusion occurs due to increased vascular permeability in response to inflammation, combined with a reduction in the distance between joint capillaries and the joint space secondary to joint capsule stretch (Figure 2). An osmotic gradient may also occur in response to increased levels of protein and cellular content within the synovial fluid.Where the joint capsule attaches to bone, enthesiophytes develop, and osteophytes form at the articular margin. Over time these enlarge and ossify becoming evident radiographically. Within the subchondral bone, trabeculae respond to the higher loads and become dense and irregular leading occasionally to radiographic signs of sclerosis. This more dense bone cannot distribute the forces of normal load from the cartilage.The fact that pathologic changes occur in all tissues of the joints, including changes in ligaments, periarticular muscles, nerves and fat pads has led to the concept of the joint being an organ, and OA as a disease that leads to organ (joint) failure (Loeser, 2012).Osteoarthritic PainThe chronic pain that is associated with osteoarthritis differs from the acute pain present following orthopaedic surgery (Fox & Downing, 2014) and pharmacological treatment of the condition reflects this. Pain within the joint is multifocal, coming from direct stimulation of the joint capsule and bone receptors by cytokines and inflammatory mediators, physical stimulation of the joint capsule by effusion and stretch mechanisms, physical stimulation of the bone from abnormal loading and physical stimulation of tendons, muscles and ligaments (Fox & Millis, 2010). Whilst medical management and treatment of OA will be covered in the next article, the following is a brief summary of the concepts believed to be involved in the development of OA pain. Further details of the pain pathway and chronic neuropathic pain can be found in a number of other relevant references (Fox & Millis, 2010; Gaynor & Muir III, 2015; Lascelles, 2012; Mathews, 2008; Meintjes, 2012; Muir & Woolf, 2001; Shilo & Pascoe, 2014)Nociceptive pain is a sensory experience that occurs in acute response to tissue injury and inflammation. It is an adaptive function of the neurologic system that signals the type and location of an injury and in essence warns the individual there is an injury present (Mathews, 2008). Synovial joints contain A-, A- and C- nerve fibres. The A-fibres are present in the tissues surrounding the joint such as ligaments and the fibrous joint capsule and free nerve endings are present in all tissues except articular cartilage. Innocuous sensation and low-intensity stimuli e.g. touch or vibration, are transmitted by these fibres from the periphery to the CNS. Normally these fibres do not contribute to the pain pathway. In response to injury however, A- afferents conduct noxious or mechanical input. These fibres are responsible for the initial, localised sensation of pain and warn the body to move away from the stimulus. If the stimulus increases, slower C-fibres are recruited causing the more throbbing or burning pain.Inflammatory painIf tissue injury is enough to stimulate inflammation, causing release of inflammatory mediators into the joint, the C-fibres continue to produce afferent discharges and contribute to ongoing pain. Inflammatory cells release TNF-, IL-6 bradykinin, prostaglandins and neuropeptides, increasing the afferent nociceptive stimulus to the spinal cord and stimulating hyperalgesia in a process termed peripheral sensitisation (Shilo & Pascoe, 2014).Neuropathic painNociceptive input from the periphery is processed within the dorsal horn of the spinal cord. If the initial pain stimulus continues to present to the CNS, for example, in cases of untreated or inadequately treated peripheral pain, wind-up occurs through release of glutamate from spinal cord neurons. N-methyl D-aspartate receptors are activated by glutamate and ion channels open, depolarising the post-synaptic membrane and leading to a central sensitisation (Lascelles, 2012). In addition to this, phospholipases contribute to this wind-up amplifying the activity of the NMDA receptors, an effect that may last hours to weeks and in some reported cases years (Muir & Woolf, 2001).DiagnosisHistory and physical examinationA detailed history is paramount in the diagnosis and assessment of the severity of osteoarthritis. Signs of disease reported by owners are often non-specific. The history can be acute or chronic with signs being intermittent or continuous. In many cases previous joint injury or disease of the affected joint will be reported. One of the signs most commonly noted by owners is stiffness of their dog after rest and this often precedes the development of overt lameness. Some dogs show reluctance to exercise, reduced ability to jump or climb stairs and occasionally behavioural changes. The clinical signs may vary at different times of the day, with differing amounts of exercise and with changes in the weather (Innes, 1998).In cats, where the disease process is often idiopathic or due to aging, owners may not notice any signs, or there may be a subtle reduction in the activity of the cat and a reluctance to jump or play. Some cats will show signs of aggression and they may develop signs such as an unkempt or matted coat due to reduced grooming activity. Stiffness may or may not be reported (Perry, 2014; Lascelles, 2010).Clinical findings may also be varied. In secondary OA, where there is an underlying cause, signs referable to the primary disease may also be evident, for example positive cranial drawer in a dog with cranial cruciate ligament disease. In addition to stiffness when rising or after rest, lameness and gait alterations are often evident. Joint pain and swelling, joint effusion, reduced range of motion (ROM), instability, crepitus and muscle atrophy are often noted (Renberg, 2005). In cats, it may be challenging to perform a full assessment of each joint and activity assessments may be useful to localise pain (Bennett et al., 2012).Diagnostic imagingRadiography gives an indication of the bony change associated with OA such as osteophytosis, sclerosis and bony remodelling. However, often radiographic signs do not correlate with the clinical signs the patient is showing (Fox & Millis, 2010) and it is important to remember to treat the patient, not the radiograph. Radiographic features of the disease may include: osteophytosis, enthesiophytosis, joint effusion, soft tissue swelling, subchondral sclerosis, intra-articular mineralisation and subchondral bone cysts (Figure 3). In some cases, and especially in cats, the clinical signs and cartilage lesions may be present with minimal or no radiographic change, whilst in others significant OA radiographic changes may exist with little or no evidence of clinical disease (Bennett, 2010). Gordon et al (2003) concluded that the presence of OA within the stifle joint of dogs does not correlate with clinical function and radiographic function should not be used as a predictor of clinical outcome (Figure 4).Whilst radiography is the most commonly used imaging modality for diagnosing OA, advanced imaging techniques such as CT and MRI can be used to classify the disease further. MRI is a useful method of evaluating the soft tissues of a joint, including ligaments, tendons, menisci and synovium and has been reported in one study to reveal degenerative joint changes such as minor effusion, osteophytosis and cartilage thinning in cats with no radiographic evidence of disease (Guillot et al., 2012). CT is useful to evaluate joints with complex anatomy such as elbows, carpi and tarsi and is very sensitive for the detection of osteophytes by avoiding the superimposition of these structures seen radiographically through cross-sectional imaging (Innes, 2012). Arthroscopy is a widely available and sensitive diagnostic tool to evaluate the surface characteristics of articular cartilage and other intra-articular structures such as the synovium, menisci and ligaments. Subjectively, cartilage lesions are graded using the modified Outerbridge cartilage scale (Box 1) (Schulz, 2003). Whilst arthroscopy is a useful way of grading and comparing cartilage lesions, it does not necessarily correlate with histologic measures of disease. Goldhammer et al (2010) demonstrated that in cases of medial coronoid disease, radiographic scoring of osteophytosis and arthroscopic scoring of visual cartilage damage correlated moderately well with histopathologic evaluation of cartilage damage on the coronoid process and synovial inflammation in the medial part of the joint, but not with bone pathology in the medial coronoid process.Arthrocentesis and analysis of the synovial fluid is a very useful and minimally invasive method of classifying the type of joint disease present, easily performed in practice. The technique allows differentiation between degenerative conditions and more inflammatory arthopathies such as immune-mediated arthritis and sepsis (Box 2). In most cases of OA there will be mild inflammatory change evident, characterised by an altered volume of synovial fluid with reduced viscosity and increased white cell count with mononuclear cells dominating.ConclusionOsteoarthritis is a complex disease with a multifactorial aetiology. Whilst diagnosis of the condition is usually straightforward, management of it is not. The next article will discuss surgical and non-surgical options for managing the osteoarthritic patient, including adjunctive therapies and the evidence behind them.ReferencesBennet D (2010) Canine and feline osteoarthritis. In: Ettinger SJ & Feldman EC, 7th Ed. Missouri: Elsevier pp. 750-761Bennett D, Zainal Ariffin SM, Johnston P (2012) Osteoarthritis in the cat: How common is it and how easy to recognize? J Fel Med Surg 14(1): 65-75Clements D (2006) Arthrocentesis and synovial fluid analysis in dogs and cats. In Practice 28: 256-26Fox SM & Downing R (2014). Rehabilitating the painful patient: pain management in physical rehabilitation. In Millis DL & Levine D: Canine Rehabilitation and Physical Therapy, 2nd ed. Elsevier-Saunders, Philadelphia: 243-253Fox SM & Millis D (2010) Multimodal management of canine osteoarthritis. London: MansonGaynor JS & Muir III WW (2015) Handbook of veterinary pain management. Missouri: ElsevierGoldhammer MA, Smith SH, Fitzpatrick N & Clements DN (2010) A comparison of radiographic, arthroscopic and histological measures of articular pathology in the canine elbow joint. The Vet Journal 186: 96-103Goldring MB & Goldring SR (2010) Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Annals of the New York Academy of Sciences 1192: 230-237Gordon WJ, Conzemius MG, Riedesel E, Besancon MF, Evans R, Wilke V & Ritter MJ (2003) The relationship between limb function and radiographic osteoarthrosis in dogs with stifle osteoarthrosis. Vet Surg 32: 451-454Guillot M, Moreau M, d’Anjou M-A et al (2012) Evaluation of osteoarthritis in cats: Novel information from a pilot study. Vet Surg 41 (3): 328-35Hardie EM, Roe SC & Martin FR (2002) Radiographic evidence of degenerative joint disease in geriatric cats: 100 cases (1994-1997). J Am Vet Med Assoc 220(5): 628-632 Innes J, Barr A (1998) Can owners assess outcome following surgical treatment of canine cranial cruciate ligament deficiency? J Small Anim Pract 39:373-378Innes J (2012) Arthritis. In Tobias K. M. & Johnston S. A. (Eds) Veterinary Surgery Small Animal, Missouri: Elsevier, pp. 1078-1111Johnston SA (1997) Osteoarthritis: joint anatomy, physiology and pathoiology. Vet Clin North Am Small Anim Pract 27(4): 699-723Lascelles BDX (2010) Feline degenerative joint disease. VetSurg 39: 2-13Lascelles B. D. X (2012) Surgical Pain: Pathophysiology, assessment and treatment strategies. In: Tobias K. M. & Johnston S. A. (Eds) Veterinary Surgery Small Animal, Missouri: Elsevier, pp. 237-247Loeser RF, Goldring SR, Scanzello CR & Goldring M (2012) Osteoarthritis: A disease of the joint as an organ. Arthritis & Rheumatism 64: 1697-1707Mathews KA (2008) Neuropathic pain in dogs and cats: if only they could tell us if they hurt. Vet Clin North Am Small Anim Pract 38(6): 1365-414Meintjes RA (2012) An overview of the physiology of pain for the veterinarian. The Vet Journal 193: 344-348Muir WW III, Woolf CJ (2001) Mechanisms of pain and their therapeutic implications. JAVMA 219 (10): 1346-56Perry KL (2014) The lame cat: the challenge of degenerative joint disease. Companion Animal 19: 518-525Renberg WC (2005) Pathophysiology and management of arthritis. Vet Clin North Am Small Anim Pract 35: 1073-1091Schulz KS (2003) What’s new in elbow arthroscopy. In: Proceedings of the 13th Annual American College of Veterinary Surgeons Symposium, Washington DC, October, pp. 329-333Shilo Y & Pascoe P. J. (2014) Anatomy, physiology and pathophysiology of pain. In: Egger C. M., Love L. & Doherty T. J. (Eds) Pain management in veterinary practice, Oxford: Wiley Blackwell, pp. 9-27Sutton S, Clutterbuck A, Harris P, Ghent T, Freeman S, Foster N, Barrett-Jolley R & Mobasheri A (2009) The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis. The Vet Journal 179: 10-24Van Ryssen B, vanBree H, Dimoens P (1993) Elbow arthroscopy in clinically normal dogs. Am J Vet Res 54: 191-198Box 1: Scoring of articular cartilage lesions based on their arthroscopic appearance Modified Outerbridge ScoreArthroscopic description of cartilage condition0Normal1Chondromalacia2Partial thickness fibrillation3Deep ulceration, not reaching subchondral bone4Full thickness cartilage loss exposing subchondral bone5Eburnated boneAdapted from Van Ryssen et al., 1993Figure 1:Arthroscopic image of the canine elbow (Courtesy of Dr Karen Perry, University of Michigan)Severe cartilage erosion is seen at the edge of the medial coronoid process and over the medial condyle, exposing the subchondral bone (red). The medial and lateral condyles have been labelled as have the radial head and ulna.Figure 2:Lateral view of the stifle of a dog with acute cranial cruciate ligament ruptureNote the effacement of the intra-articular fat pad by joint effusion. Minimal osteoarthritic change is present at this time. In more chronic cases osteophytosis of the distal pole and the fabellae would be evident and intra-articular mineralisation may develop.Figure 3:Medio-lateral (3a) and craniocaudal (3b) views of the elbow of a dog suffering severe osteoarthritis (Courtesy of Dr Karen Perry, University of Michigan)Severe osteophytosis is present with sclerosis of the ulnar notch and bone remodelling over the anconeal process, medial coronoid process, radial head and both epicondyles. There is the appearace of soft tissue swelling visible on the medio-lateral view.Figure 4:Ventrodorsal radiograph of the hips of a 7 year-old Springer Spaniel with hip dysplasia and severe bilateral osteoarthritisThis dog was presented for total hip replacement, however following a period of medication and exercise modification clinical signs resolved negating the requirement for surgery.Figure 1Figure 2Figure 3aFigure 3bFigure 4 ................
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