17/08/2024
Just published 💥
How to Distinguish Non-Inflammatory from Inflammatory Pain in Rheumatoid Arthritis (RA)?
👉 Rheumatoid arthritis is a chronic, inflammatory, autoimmune disease that mainly affects joints but is known to have extra articular effects on pulmonary, nervous and cardiovascular systems. (https://pubmed.ncbi.nlm.nih.gov/22150039/)
👉 In RA, pain is often disproportionate to disease activity measures and frequently persists even where clinical, biochemical and imaging evidence of inflammation has resolved. (https://pubmed.ncbi.nlm.nih.gov/32841455/)
📘 In a brand-new publication, Khot and colleagues outline the latest research relevant to distinguishing non-inflammatory from inflammatory RA pain and review the current understanding of its neurobiology and management. (https://pubmed.ncbi.nlm.nih.gov/39120749/)
👉 The authors use the term 'inflammatory pain' to describe pain that is proportionate to the level of RA activity, as measured by inflammatory markers and joint imaging, and 'non-inflammatory pain' to describe pain disproportionate to RA presentation.
🔥 Inflammatory joint pain in RA is a type of nociceptive pain initiated by pro-inflammatory mediators such as prostaglandins, bradykinins and neurotrophic growth factors released during synovial inflammation (https://pubmed.ncbi.nlm.nih.gov/11460811/). These proinflammatory mediators induce an inflammatory cascade and the synoviocytes interact with cells of the adaptive and innate immune system further causing a hyperplastic synovium, bone erosions and cartilage destruction. (https://pubmed.ncbi.nlm.nih.gov/29736302/).
🔥 Nociceptors innervating the synovium and subchondral bone are responsible for arthritic pain; these include joint nociceptors specialised in the detection of chemical stimuli, including the above inflammatory mediators, as well as mechanical or thermal noxious stimuli (https://pubmed.ncbi.nlm.nih.gov/30128836/). Inflammation sensitises nociceptors to noxious and innocuous stimulation reducing firing thresholds.
🔥 Inflammatory pain tends to be worse after inactivity so typically early morning (> 30 min). It is also associated with stiffness. Joint swelling and tenderness are the signs and symptoms of synovial membrane inflammation following immune activation and can be elicited via clinical examination and imaging (e.g. joint ultrasound).
🔥 Elevations of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are consistent with the presence of an inflammatory state and can reflect the degree and extent of (local) synovitis and systemic inflammation in RA.
💡 Unsurprisingly, raised CRP levels are also associated with greater pain in RA (https://pubmed.ncbi.nlm.nih.gov/33385862/). Interestingly, systemic inflammation and autoimmunity are detectable several years prior to the onset of detectable joint inflammation (https://pubmed.ncbi.nlm.nih.gov/24247116/) and autoantibody positivity and pain is highly predictive for development of RA (https://pubmed.ncbi.nlm.nih.gov/26395501/), suggesting pain symptoms may precede diagnosis of RA, and highlighting the nuanced dichotomy of inflammatory and non-inflammatory pain.
🧠 A third of patients diagnosed with RA report significant and severe widespread pain (out of proportion to measures of systemic inflammation (https://pubmed.ncbi.nlm.nih.gov/32841455/). This out-of-proportion pain is often labelled 'non-inflammatory'.
🧠 Non-inflammatory pain in RA rarely presents in isolation but instead is usually found alongside inflammatory pain aetiologies in something of a continuum. There is evidence that non-inflammatory and inflammatory pain share common aetiologies during the earlier stages of the disease, with pro-inflammatory pathways causing hyper-nociception in early RA and providing an environment for the potential development of nociplastic pain.
🧠 Non-inflammatory pain in rheumatoid arthritis (RA) is maintained via altered nociceptive processing in the central nervous system (CNS). This manifests as pain out of proportion to underlying RA disease activity, including nociceptive amplification from joint inflammation and from typically innocuous stimuli (e.g. pressure delivered to non-joint regions, such as the medial border of the scapula).
🧠 Nociplastic pain mechanisms are often obscure, however risk factors for nociplastic pain are well described: family history, past pain experience, and psycho-social factors including psychological, emotional and physical trauma, are all recognised to increase the risk of developing nociplastic pain. An 'initiating' risk-factor may be considered a 'trigger', and include stressors that might be psychosocial, or as is often the case for secondary fibromyalgia in RA, underlying inflammatory disease (https://pubmed.ncbi.nlm.nih.gov/34062144/). Pain severity disproportionate to RA disease activity, disabling fatigue, sleep disturbances or unrefreshed sleep, mood disturbances/disorders, neuropathic symptoms, brain fog, worsening physical and mental health, are all clues indicative of nociplastic pain. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886964/, https://pubmed.ncbi.nlm.nih.gov/27659057/)
💡 Maintaining a high index of suspicion for presence of non-inflammatory pain in early RA is key to instituting an early biopsychosocial approach to patient assessment and promoting appropriately combined pharmacological and non-pharmacological therapeutic modalities early in the course of their disease (https://pubmed.ncbi.nlm.nih.gov/34062144/, https://pubmed.ncbi.nlm.nih.gov/37372912/). The NICE Chronic Pain Guidelines visual summary is helpful here (s. comments, https://www.nice.org.uk/guidance/ng193/resources/visual-summary-pdf-9073473517, https://www.nice.org.uk/guidance/ng193).
📷Illustration: Mechanisms of non-inflammatory pain in RA, https://pubmed.ncbi.nlm.nih.gov/39120749/
