Chapter 66Noninfectious Arthritis
Noninfectious arthritis is characterized by pain, heat, swelling (effusion), erythema, and lameness. Joint structure and function, aspects of diagnosis and management of joint disease, and osteoarthritis (OA) are discussed in Chapters 61 and 84. This chapter focuses on normal and abnormal joint physiology and other specific noninfectious joint diseases.
Fluid flow from the vascular space into the interstitium and joint space (third compartment space) and out into venules and lymphatics is tightly governed by Starling forces, which are a balance of arterial and venous pressures and colloid osmotic forces across the joint. The resultant fluid flow through the joint is modified by permeability of the synovium (osmotic reflection coefficient) and the vessel surface area available for fluid transport (filtration coefficient). Even in normal joints these forces are influenced by gravity (joint dependency), motion (exercise), and structure (joint compliance).1-7
Horses are unique in needing joint motion to maintain isogravimetric states of the joints (no fluid gain or loss), especially in peripheral joints.1 In normal stationary equine limbs, lymphatic drainage from joints approximates zero until joint pressure exceeds 11 mm Hg for the fetlock joint (transitional microvascular pressure). In standing animals without counter forces, such as motion or external bandages to increase lymph flow forces, gravitational pressures increase arterial pressure to the joint and venous and lymphatic pressure from the joint. The result is tissue edema and joint effusion.
The balance of these forces is altered in horses with synovitis because of the increased blood flow, altered synovial permeability, structural joint capsular changes, and loss of joint motion because of pain.1,3,5,8,9 These factors profoundly affect joint physiology, contribute to clinical signs, and result in damage to the synovium and articular cartilage. Early signs of effusion that precede clinical detection of inflammation are related to changes in the hemodynamics of the joint, including increased blood flow and reduced joint motion.8,9
In chronic arthritis, capsular thickening, fibrosis, and altered synovial function likely influence fluid dynamics. Capsular fibrosis and joint enlargement produce decreased tissue compliance, and an increase in intraarticular pressure occurs, even with slight increases in joint effusion. Articular cartilage is avascular and depends on synovial fluid for nutrition, so alteration in fluid flux affects nutritional exchange between the articular cartilage and synovium. Reduced nutrition exchange to articular cartilage exacerbates articular surface fibrillation and degenerative changes.10,11
Increased blood flow and capillary leakage occur early and contribute to increased fluid volume in the joint interstitium and synovial fluid, recognized as effusion. The condition is stimulated by vascular changes and neurotransmitter release, particularly α2-adrenergic stimulation.2,8,9 Because of low intraarticular pressures in normal equine joints (−5 mm Hg6; −1.25 mm Hg12), effusion precedes interstitial edema, until intraarticular pressure is greater than 11 mm Hg.1 These physiological circumstances make detection of effusion one of the most sensitive indicators of early joint stress. Effusion, although common, is not normal and alters joint function. Congruent motion of joint surfaces depends on normal negative pressure and is important in decreasing shear force (side-to-side, sloppy movement).7 Effusion is not painful as long as capsular tension is normal. Through the phenomenon of creep-relaxation, capsular tension is reduced in distended joints. Normal joints are relatively compliant and can accommodate fairly large changes in fluid volume with minimal increase in pressure, but elastance profiles of these joints may be permanently altered.13 Joints with high structural congruence, such as the tarsocrural joint, are less affected biomechanically by joint effusion than are less congruent joints.7
High synovial fluid volume becomes more important during joint motion. Joint pressure profiles are profoundly altered by joint angle.6,7,13 With effusion, as initial intraarticular pressure is increased, the capacity to accommodate rapid changes in pressure goes down, causing a rapid rise in intraarticular pressure and capsular wall tension at extreme joint angles, resulting in sharp pain during maximal joint excursion and simultaneous reduction in synovial perfusion.14 These effects could be present even if synovitis is not recognized clinically. The influence of intermittent synovial ischemia is not elucidated fully, but it may be important in diseases of synovial proliferation.
Inflammation causes a humoral (vascular) and a cellular response. In early arthritis, cells are up-regulated to produce inflammatory mediators. Gene transcriptional profiles may be unique to certain forms of arthritis and potentially could be used in the future to recognize and prevent arthritis. Up-regulation of genes causes protein production, initiation of the inflammatory cascade, and further release of inflammatory mediators. Important mediators include cytokines interleukin-1, interleukin-6, and tumor necrosis factor.2-4,15,16 Secondary mediators such as the eicosanoids (prostaglandin E2 and leukotrienes),2-4,15 free oxygen radicals,17 substance P,3 and nitric oxide3,4 are also proarthritic and amplify pain.
Cellular influx causes effusion and subsequent clinical recognition of synovitis. The degree of synovitis and articular cartilage damage are directly proportional to synovial fluid nucleated cell count in infectious and noninfectious arthritis. Neutrophils are highly migratory and can move into joint fluid within 3 hours after a chemotactic stimulus, such as with the introduction of interleukin-1, paclitaxel, or endotoxin.2,8,9,15,18 These cells are damaging to surrounding tissue because they have destructive enzymes and alter the synovial fluid environment. In noninfectious arthritis, nucleated cell count is usually less than 30,000 nucleated cells/mcL,15 but values greater than 100,000 nucleated cells/mcL occur in autoimmune arthritis,19 in endotoxin-induced arthritis,16,20 and early in reactive arthritis.
Intraarticular pressures greater than 30 mm Hg cause significant reduction in the perfusion of the synovium and fibrous layer of the joint capsule.14 Pressures of this magnitude occur in horses with palpable effusion of the fetlock joint and are present when synovitis is prominent.12 Pressures greater than 60 mm Hg can reduce blood flow profoundly, and pressures approximating 100 mm Hg can cause capsule joint rupture (carpus and fetlock21). Clinically, joint rupture is uncommon but was hypothesized to contribute to dorsal fetlock capsular thickening.12 I have seen this as a rare occurrence in the plantar pouch of the tarsocrural joint and the palmar pouch of the antebrachiocarpal joint. Intraarticular pressure can reach high levels during maximal flexion and extension, particularly in horses with resting pressures greater than 30 mm Hg.6 Ischemia has been hypothesized to be a component of synovitis, particularly in the proliferative form.22 Low oxygen tension stimulates angiogenesis and granulation tissue formation, resulting in fibrosis. In chronically inflamed joints, clubbed and thickened synovial membrane often is seen during arthroscopic surgery, supporting the concept of synovial ischemia.
Synovial cells produce hyaluronan. A protective layer of high-concentration hyaluronan remains close to the surface of the synovium, and the remainder diffuses into the joint space, creating the unique viscosity of synovial fluid.3,7 Adequate hyaluronan concentration is critical to provide lubrication of synovial soft tissues, particularly synovial villi. During inflammatory synovitis, lubrication of the soft tissues is reduced because of dilution of hyaluronan and a reduction in hyaluronan production. Swollen, edematous villi cause an elevated coefficient of friction. In horses with mild effusion, hyaluronan concentration can be normal because increased production by synovial cells matches elevation in synovial fluid volume.23 When inflammation increases, synovial cell production decreases and degradation of hyaluronan increases. In horses with severe joint inflammation or hemarthrosis, hyaluronan concentration may be negligible.
Sensory and motor innervation help maintain joint stability, and in the absence of these protective reflexes, severe arthropathy may develop.24 When activated, the peripheral nervous system can initiate the major features of acute inflammation, such as vasodilation and effusion, and lower the threshold for pain.25 The C and A nerve fibers responsible for pain sensation in arthritis are activated by amines (such as serotonin) and neuropeptides (calcitonin gene-related peptide and substance P) that also act locally to exert proinflammatory effects on synovium. A role of substance P in joint pain is supported by the clinical effectiveness of the substance P–depleting substance, capsaicin. Capsaicin initially activates C fibers, resulting in substance P release and pain, but subsequently desensitizes or causes degeneration of C fibers.26
The contribution of neuropeptides may be different in acute and chronic inflammatory arthritis. Edema formation in denervated limbs may indicate that loss of sensory innervation could play a role in acute arthritis.27 Increased edema formation and decreased permeability to macromolecules have been observed in denervated limbs subjected to interleukin-1 induction of synovitis.2 The role of innervation in chronic arthritis is complex, because the neuropeptide substance P and calcitonin gene-related peptide were increased in sciatic nerve, dorsal root ganglia, and periarticular tissues but were decreased in synovium.
The therapeutic implications are intriguing. Intramuscular gold or topically applied capsaicin could selectively destroy C fibers, thus lowering substance P levels, and these have been found to be clinically useful. Nonsteroidal antiinflammatory drugs (NSAIDs) decrease prostanoid production, and intraarticular corticosteroids inhibit the arachidonic acid cascade, thus having direct and indirect effects.28 In addition, stimulation of primary afferent nociceptive fibers causes release of glutamate and substance P from central spinal pathways. This nociceptive input can be inhibited by stimulation of proprioceptive and tactile type I and II fibers. Stimulation of these fibers can be accomplished by high-frequency, low-intensity transcutaneous neural stimulation, frequently used in physiotherapy.
Rheumatoid arthritis is a steroid-responsive arthritis, associated with high synovial nucleated cell counts, progressing to bone erosion and pannus formation. For establishment of a diagnosis of rheumatoid arthritis, an autoimmune component and production of rheumatoid factor must be documented. According to these criteria rheumatoid arthritis has not been reported in horses. In human systemic lupus erythematosus (SLE), systemic disease is also present, and autoantibodies are directed toward nuclear cellular material. An SLE-like disease has been described in a young horse.29 In horses, anti–collagen type II antibodies and immune complexes have been identified in synovial fluid of horses with OA and joint trauma. However, these immune complexes are much less common in horses with mild synovitis and have been found in sera. Relationship of cause and effect of these immunological findings is unclear, because immune complexes are found in many disease types. Although these autoantibodies may be associated with equine diseases, it is unlikely that they initiate arthritis in horses.30 They may develop after exposure to type II collagen, after articular cartilage trauma, or with wear. Specific assays of synovial fluid for immunoglobulin M–rheumatoid factor (a feature of rheumatoid arthritis), antibodies to heat-shock protein, and antinuclear antibodies (ANAs), a feature of SLE, reveal only modestly low levels of rheumatoid factor without correlation to disease and no ANAs.31
The presence of synovitis and immunoglobulin G complex deposition in the synovium of foals has been reported.32-34 This form of synovitis is called immune-mediated arthritis and may be associated with circulating immune complexes formed as a result of systemic disease.32 Using specific monoclonal antibody techniques, immune-mediated arthritis was diagnosed in a 6-week-old pony foal infected with equine herpesvirus–4.33 Three horses were hyperimmunized with Streptococcus equine M protein vaccine and subsequently injected intraarticularly with purified streptococcal M protein. Severe suppurative synovitis developed, and synovial fluid nucleated cell counts were greater than 100,000 cells/mcL.34 Eosinophils were prominent in the synovial fluid and synovial membrane in two horses.
A clinical syndrome of polysynovitis and vasculitis secondary to high circulating M protein (after streptococcal infection), or associated with Rhodococcus equi infections, is recognized and thought to be caused by immune-mediated arthritis. Seventeen (35%) of 48 foals with R. equi pneumonia infection had chronic active noninfectious arthritis. Pathogenesis involves immunocomplexes in the synovium. The hallmark of immune-mediated arthritis in foals is effusion in one or more joints but minimal lameness.35 Synovitis often resolves in several weeks with or without treatment. Foals should be restricted to box rest, but no other specific treatment is necessary. Corticosteroids are contraindicated, because bacterial infection may be perpetuated.
Reactive synovitis may occur after intraarticular injection of any product. Any intraarticular injection incites at least mild synovitis. The activated drug or a product in the solution may chemically induce reactive synovitis. Endotoxin contamination of multiple-dose vials or even single-dose products may cause reactive synovitis. In the case of a multiple-dose vial, a suspicion of endotoxin contamination should be high if more than one horse shows clinical signs within a short period. Horses are exquisitely sensitive to endotoxin, and concentrations above 0.125 ng per joint incite synovitis.36 After intraarticular injection of methylprednisolone acetate, inflammatory cells surrounding vehicle crystals were identified in synovium 6 weeks later.37 Reactive synovitis associated with methylprednisolone acetate may be most common in the distal interphalangeal joint. Although unusual, within a few hours after injection, horses can show severe lameness. Steroid arthropathy may be a form of reactive synovitis. The distal interphalangeal and tarsocrural joints appear most at risk to develop reactive arthritis after intraarticular injection of polysulfated glycosaminoglycans.38
Reactive synovitis must be distinguished from early infectious arthritis. Distinguishing features of reactive arthritis include early onset after injection (about 24 hours), synovial nucleated counts less than 30,000 cells/mcL, and resolution of clinical signs within 1 to 3 days. Lameness ranges from mild to severe, and in some horses distinguishing reactive arthritis from infectious arthritis may be difficult, and prompt management with intraarticular lavage, systemic and local antimicrobial drug administration, and antiinflammatory therapy should be instituted. Culture and susceptibility testing should be performed if any suspicion exists that a bacterial infection is present, if synovitis does not resolve quickly, or in horses in which lameness persists.
Eosinophilic synovitis is rare and may represent an allergic reaction to an injected product, or to parasite migration, or could be truly idiopathic.34,39 Joint lavage to assist in removing foreign material, and the administration of NSAIDs and anthelmintic treatment are indicated.
Foreign bodies rarely may be present within a joint or tendon sheath and incite chronic reactive synovitis. Broken needles, plant or seed awns or thorns, and debris from nearby wounds can cause reactive synovitis. Radiological and ultrasonographic examinations can be helpful to identify the nature of the foreign material.40 Cellulitis close to a joint may cause reactive synovitis that resolves with successful treatment of the primary infection.
Primary traumatic synovitis is an early form of OA. Horses at risk are usually in active sports training. Lameness usually is managed by intraarticular and systemic medication. Early medical intervention and appropriate joint rest and physiotherapy are critical to prevent loss of glycosaminoglycan from articular cartilage and permanent joint wear. Early loss of articular cartilage proteoglycan is reversible with medication and joint rest. If training is continued, some horses will develop proliferative synovitis, chip fractures, intraarticular ligament injury, and OA. Intermittent hemarthrosis (see later) may be detected with primary traumatic synovitis, but often it indicates injury to subchondral bone, such as chip fracture or cartilage elevation.
Chronic traumatic synovitis and continued exercise result in a painful thickening of the synovium, proliferative synovitis, particularly in areas of compression trauma.41-45 The most common location is the dorsal fibrous pad (synovial pad) of the metacarpophalangeal joint, directly under the broad, flat common digital extensor tendon and joint capsule.41 At maximal extension and flexion, pad compression results in intrasynovial hemorrhage, granulation tissue formation, fibrosis, and mineralization. Diagnosis and management are discussed in Chapter 36.
Chronic proliferative synovitis is a frequent finding in the carpal and tarsocrural joints during arthroscopic examination. Diffuse proliferative synovitis can be seen in horses that have had frequent intraarticular injections and have continued in exercise. Capsular fibrosis and loss of fine villous architecture occur. I do not recommend radical synovectomy, but removal of fibrotic tufts of capsule and synovium prone to pinching or demonstrating signs of internal hemorrhage and edema is warranted.
See Chapters 54 and 56 for a discussion of osteochondrosis.
Synovitis can occur without any known cause or associated trauma and can be truly idiopathic, although synovitis may be related to circulating toxins, including endotoxin, streptococcal cell wall, M protein, and viruses. In people, bacterial and viral deoxyribonucleic acid and bacterial peptidoglycans have been located in joints of patients with early rheumatoid and other noninfectious arthritides.46,47 In horses synovitis can be associated with vasculitis, such as that seen with equine viral arteritis.
Bleeding into a joint (hemarthrosis) causes joint capsule distention, severe pain, and lameness.48 Draining the blood from the joint usually results in rapid relief of clinical signs. The cause of hemorrhage may be trauma to proliferative hemorrhagic synovium, an intraarticular fracture, or tearing of an intraarticular ligament. Hemorrhage may occur on a single occasion or may be recurrent. Diagnosis of hemorrhage is simple, by arthrocentesis, but identification of the primary cause can be more difficult. In the absence of radiological abnormalities, exploratory arthroscopy is warranted in a horse with recurrent episodic severe lameness associated with hemarthrosis. Hemorrhage associated with proliferative synovitis may be managed successfully by subtotal synovectomy. (Editors’ note: hemarthrosis appears to most commonly affect the antebrachiocarpal and tarsocrural joints but rarely can involve other joints such as the middle carpal joint.)
Although strictly speaking an infectious disease, Lyme disease is discussed in this section because it should be considered a differential diagnosis in tick-endemic areas in a horse with shifting limb lameness associated with synovitis in several joints.49,50 However, many clinically normal horses have antibody titers to Borrelia burgdorferi, and high titers are not synonymous with clinical disease.51 Authentic Lyme disease is poorly documented in the horse, and definitive diagnosis would require identification of substantially raised titers in paired serum samples. Tetracycline most effectively eliminated positive cultures and antibodies to Borrelia as compared with use of doxycycline or ceftiofur.52