Protective effect of sensory denervation in inflammatory arthritis (evidence of regulatory neuroimmune pathways in the arthritic joint)

Abstract

Objective: To investigate the direct effect of joint innervation on immune mediated joint inflammation in a patient with psoriatic arthritis (PsA). Case report: The patient developed arthritis mutilans in all digits of both hands with the exception of the left 4th finger, which had prior sensory denervation following traumatic nerve dissection. Plain radiography, ultrasonography and nerve conduction studies of the hands confirmed the absence of articular disease and sensory innervation in the left 4th digit. Methods: This relationship between joint innervation and joint inflammation was investigated experimentally by prior surgical sensory denervation of the medial aspect of the knee in six Wistar rats in which carrageenan induced arthritis was subsequently induced. Prior sensory denervation-with preservation of muscle function-prevented the development of inflammatory arthritis in the denervated knee. Discussion: Observations in human and animal inflammatory arthritis suggest that regulatory neuroimmune pathways in the joint are an important mechanism that modulates the clinical expression of inflammatory arthritis.A 60 year old woman presented with psoriasis, which she had had since age 16, and psoriatic arthritis (PsA) since age 45. Initial involvement of the right hand had progressed to an inflammatory polyarthritis, affecting the small joints of both hands and both knees, and to dactylitis of the toes but without spondylitis or sacroiliitis. Current drug treatment comprised methotrexate and rofecoxib and there were no signs of active synovitis of the hands, either upon clinical examination or by laser Doppler imaging. 1 On examination the patient was noted to have established arthritis mutilans of the metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints of the hands with complete sparing of the left 4th digit ( fig 1A). Of note the left palm had been lacerated as a child-before the onset of skin or joint disease-with consequent nerve injury and loss of sensation in the left 4th finger. The left 4th digit was noted to be hypoplastic with a normal range of active and passive movement but with loss of soft touch, pinprick, and vibration sensation along the entire digit distal to the laceration. Investigations were consistent with inactive PsA (rheumatoid factor negative, C reactive protein ,6 mg/l, erythrocyte sedimentation rate 1 mm/1st h).Plain radiography of the hand confirmed a symmetrical destructive arthropathy of the MCP, PIP, and DIP joints with features of bony resorption and periosteal proliferation in all digits, but with sparing of the small joints of the left 4th digit ( fig 1B). Ultrasonography-a more sensitive measure of joint inflammation and damage-of PIP joints in the right and left 4th digits demonstrated proliferative changes in the right 4th digit but not in the left 4th digit ( fig 1C). Nerve conduction studies confirmed the complete absence of sensory innervation in the left 4th digit. On stimulation of the 4th digit no reproducible sensory r...

A peripheral neuroimmune link: glutamate agonists upregulate NMDA NR1 receptor mRNA and protein, vimentin, TNF-α, and RANTES in cultured human synoviocytes

“…Thus, in human acute and chronic arthropathies, the elevated levels of synovial fluid EAA (31, 32) from damaged cellular tissue and EAA shown experimentally to be derived from the nerve terminals (25) could activate glutamate receptors expressed locally on synoviocytes to enhance cellular activation, inflammation, and pain states. Diminution of joint edema and allodynic behaviors by 50% or more with glutamate receptor blockade in the spinal cord, afferent nerve lesion, or intra-articular glutamate antagonists provides support for the role of neurotransmitter glutamate release in significantly impacting inflammatory events occurring in the joint (19,23,37,44,49).…”

“…In subsequent studies, data were provided showing that 1) peripheral tissue damage releases glutamate and other neurotransmitter amino acids in the spinal cord, 2) dorsal horn sensitization mechanisms ensue, creating reverse sensory nerve firing directed toward the periphery, 3) neurotransmitter substances are release into the periphery, and 4) enhanced peripheral inflammation and nociceptive responses interpreted as pain continue in a vicious feedforward cycle (3, 22, 25, 31, 32, 36 -38, 40, 43-54, 57-59, 61-63). In fact, it has been shown that joint inflammation is significantly reduced in experimental arthritis and in patients with cut peripheral nerves (19,44). Lidocaine injected into the joint to block nerve transmission also reduces glutamate release in the joint (23).…”

“…Thus in these studies we combined administration of NMDA and (Ϯ)1-aminocyclopentane-cis-1,3-dicarboxylic acid (ACPD) for coactivation of NMDA receptors on synoviocytes. Response to activation of glutamate NMDA receptors is secretion of inflammatory mediators that in turn can directly activate peripheral nerve endings and the immune response (9,18,19,24,25,56,61).Induction of experimental arthritis leads to increases in the excitatory amino acids (EAA) glutamate (Glu) and aspartate (Asp) in the spinal cord dorsal horn (45,47,48,50,54,59), as well as locally in the knee joint synovial fluid (23, 25). Elevated levels of these glutamate receptor agonists are correlated with the development and time course of inflammatory swelling and blood flow changes (24,43,49,52) and the hypersensitivity measureable electrophysiologically and behaviorally in rats, cats, and primates (3,18,21,23,37,40,43,46,53,59,62,63).…”

“…Thus in these studies we combined administration of NMDA and (Ϯ)1-aminocyclopentane-cis-1,3-dicarboxylic acid (ACPD) for coactivation of NMDA receptors on synoviocytes. Response to activation of glutamate NMDA receptors is secretion of inflammatory mediators that in turn can directly activate peripheral nerve endings and the immune response (9,18,19,24,25,56,61).…”

Reduction in serum levels of substance P in patients with rheumatoid arthritis by etanercept, a tumor necrosis factor inhibitor

“…These results suggest that substance P and GRP are involved together with cytokines in the neuroimmunomodulation that occurs in arthritic joints. It has been suggested that regulatory neuroimmune pathways in the joints are important mechanisms modulating the expression of arthritis [35]. Conversely, it has been reported that substance P and CGRP can stimulate the production of IL-1, IL-6, and TNF-a from various immune cells [33] [36][37][38].…”