Inflammation Impact on Pain in Knee Osteoarthritis
Condition: Inflammation; Osteo Arthritis Knee
MeSH terms: Osteoarthritis; Osteoarthritis, Knee; Inflammation
Study type: Interventional

Summary: 
      The aim of this study is to use gold particles as a model compound to modulate specifically
      and selectively the function of macrophages and mast cells and investigate how this modulates
      pain and pain sensitization in the osteoarthritic knee assessed by mechanistic pain
      assessment technologies
    

Detailed description: 
      Osteoarthritis (OA) of the knee and hip is the most common musculoskeletal joint disease
      worldwide. Although a major symptom of OA is chronic joint pain, which has a significant
      effect on patients' quality of life, the pain mechanisms remain largely unknown.

      Recently, clinical studies have suggested the existence of a neuropathic component in OA pain
      [5]. Accumulating evidence has been indicating that painful OA patients show peripheral and
      central sensitization [3,16]. Quantitative sensory testing (QST) is a relevant way to assess
      peripheral and central sensitization in joint pain [9]. The majority of studies have
      administered mechanical stimuli, and the most commonly used modality have been pressure. A
      recent review concluded that that people with OA have lower Pressure Pain Thresholds (PPT),
      facilitated temporal summation and impaired conditioned (CPM) compared with healthy controls
      [5]. Also, recent evidence have link QST profiles to the development of chronic pain [29,38],
      which emphasises the importance of studying the central nervous system.

      Inflammation markers have been correlated with the pain intensity [35], and systemic
      inflammation can leads to sensitization of peripheral nociceptors [1]. Recently it was
      reported that higher preoperative levels of TNF-α, MMP-13 and IL-6 in synovial fluid may
      indicate a smaller improvement in pain 2 years after TKR [15].

      Injectable solutions of gold-thio-compounds have been used to treat rheumatoid arthritis for
      nearly 100 years [13,21]. Several studies suggest that gold ions reduces pain, joint
      swelling, inflammation, and increase joint motility [24,31,33]. Gold salt therapy (auranofin;
      RidauraR) has been vetted by the FDA and approved (May 1985) and recommended by the American
      College of Rheumatology as a Disease Modifying Anti Rheumatic Drug - DMARD
      (https://www.rheumatology.org).

      Gold salts, whether injected or given orally, have been shown to be effective [33,37] in
      reducing joint pain. Studies report patients going to total remission [28] and others report
      a 30% reduction in symptoms [20,27]. In addition, Clark et al., 1997 [8] concluded in a
      Cochrane meta-analysis that systemic treatment with gold was highly effective compared to
      placebo.

      The use of gold salt given systemically have been criticized, since when gold compounds are
      made to circulate systemically via the circulatory system after oral or parenteral
      administration, the gold ions reach essentially all tissues and organs. In some patients,
      organs that are not involved in the arthritic disease, such as the kidneys, liver, and skin
      are adversely affected by gold. About 30% of patients develop such remote-organ "side
      effects" and discontinue gold treatment [20]. In addition, newer drugs have been developed
      with efficacy almost equal to gold ions in many patients, and less toxic.

      To overcome the toxicity, a method that captures the efficacy of the gold ions but eliminates
      the remote side effects have been developed[10,23]. Briefly, the method isolates the gold
      ions within the affected joints by injecting solid gold metal directly into the diseased
      joint, whereby a very slow dissolution and local diffusion deliver the therapeutic gold ions
      to affected areas within the joint. In this therapy, 99.99% pure gold implants are injected
      into the body.

      Individual single beads are implanted with a 15-16 gauge needle based on an X-ray picture in
      deeply anesthetized animals close to the capsule of the affected joint(s) (videos
      www.goldtreat.com). Over 3000 dogs, and more than 100 horses have had this treatment for
      osteoarthritis at 50+ veterinary clinics and hospitals throughout Europe. (www.goldtreat.com
      ). Success rates of 50 - 70% are quoted (www.goldtreat.com), and a double-blind, placebo
      controlled study on dogs showed improvement in over 80% of the dogs, which continues for 18
      months [18] as the gold particles remain in the joint[26].

      The systemic concentration of released gold ions is low but clinically effective and because
      the gold ions do not spread in the organism, but instead stay local, the technique is safe
      [12]. The trials to date indicate that only one local application is needed to obtain
      lifelong clinical effect [12].

      To date it is still debated how much the inflammation per se contributes to pain in
      osteoarthritis. A variety of studies have investigates various aspects such as synovitis but
      still no clear associations to pain have been found[30]. Many studies have attempted to
      modulate the effect of the inflammatory mediators on the pain receptors by e.g. interacting
      with the arachidonic acid pathways[4]. As such compounds have both peripheral and central
      effects it is difficult to use such compounds a specific modulators of specific local
      inflammatory processes. No compounds have so far been used to modulate selectively the local
      organelles specifically involved in the inflammatory processes of joint pain.

      Gold particles seems as the only known method to obtain such a local effect on one specific
      element involved in the inflammatory process - the macrophages and the mast cells.

      If a foreign object gets embedded in the body, macrophages will attack the object and digest
      it.

      If the foreign object has a diameter bigger than 20 microns the macrophage cannot engulf it.
      Instead the macrophages create a membrane on the surface of the foreign body and starts a
      chemical attack in order to dissolve it.

      If the foreign body consist of gold the macrophages will cause release of gold ions from the
      foreign body.

      Gold ions, taken up by the macrophages, causes them to malfunction[10,11,23]. As the
      macrophage is 'conductor' of the inflammatory process it causes a drastic restraint of the
      inflammation and finally bring it to a stop[22,25]. The released gold ions will be taken up
      by the macrophages themselves, but also diffuse out into the surrounding tissue where they
      are taken up by other cells as well e.g. mast cells and other connective tissue cells[7,32].
      When the gold ions accumulate in the secretory granules of mast cells it blocks histamine
      release and thereby decrease the local oedema and additionally suppresses pain.

      The amount of bio-released gold ions are related to the intensity of inflammation. Only few
      gold ions are released in immunological nonreactive tissue. This means that if a local
      inflammation that has been treated with gold implants, the increase in macrophages will cause
      an immediate inhibition of the inflammation.

      The combined effect of gold ions on macrophages and mast cells is together believed to causes
      the significant reduction in pain following treatment with metallic gold particles. If this
      principle can be validated it may provide important information for development of new and
      better treatments for e.g. joint pain.

      Recently, Seifert et al.[34] called for studies providing new insights into the mode of
      action of gold ions and suggest investigating the effects on key mechanisms involved in
      arthritis or other inflammatory conditions.
    

Intervention name(s): Gold
Intervention type(s): Other
Intervention description(s): Approximately 72000, 20-40 my-meter diameter, sterilised gold particles (=20 mg) will be provided in vials (The Berlock® Gold Implants). 5-10 ml of synovial fluid is aspirated (20G needle) from most affected OA-knee. The vial of gold particles are mixed with the synovial fluid, and the mix of gold and synovial fluid is injected intra-articularly into the patients knee.
Intervention model: Single Group Assignment
Intervention model description: Pilot study
Masking: None (Open Label)
Primary purpose: Basic Science