Rheumatoid Arthritis

Rheumatoid Arthritis

Overview

Pathophysiology Signs of RA Key Drivers Red Flags Treatment Recommendations Additional Considerations Diet and Lifestyle Clinical Assessment Footnote References

Pathophysiology:

  • Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by inflammatory polyarthritis that affects peripheral joints, particularly the small joints of the hands and feet. It is a chronic, progressive disease that, if left untreated, may lead to cartilage and bone erosions, and joint destruction, resulting in functional impairment. A clinical course of exacerbations and remissions is a characteristic presentation of RA. [1]
  • RA is a complex disease with both genetic and environmental components:
    • Genome-wide association studies have detected nearly 100 loci that are associated with RA development. The strongest association is with variants in the human leukocyte antigen (HLA) gene complex, specifically variations in HLA-DR1, HLA-DR4 and HLA-DR14 alleles. [2] Additional non-HLA loci associated with RA development involve genes that regulate the immune response, [3] including protein tyrosine phosphatase, non-receptor type 22 (PTPN22), peptidyl arginine deiminase 4 (PADI4), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), tumour necrosis factor receptor associated factor 1/complement component 5 (TRAF1-C5), signal transducer and activator of transcription 4 (STAT4), and tumour necrosis factor alpha-induced protein 3 (TNFAIP3). [4]
    • Environmental stimulus, such as infection, triggers autoimmunity in a genetically susceptible host by modifying host proteins via processes such as citrullination (arginine residues of peptides and proteins are converted into citrulline via peptidylarginine deaminase enzyme), so that they become immunogenic. While several pathogens are associated with RA, no single specific pathogen has been identified as a cause. [5]
  • RA is characterised by infiltration of lymphocytes, plasma cells, dendritic cells and macrophages into the synovial membrane of affected joints. [6]
  • Lymphoid follicles form within the synovial membrane, causing activation of T cells to produce cytokines and activation of B cells to produce autoantibodies including rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA). [7]
  • Synovial macrophages are activated by tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), produced by T cells. Macrophages produce several proinflammatory cytokines, including additional TNF-α, interleukin-1 (IL-1) and IL-6, which act on synovial fibroblasts to produce further cytokines. [8]
  • The synovial fibroblasts proliferate, causing synovial hypertrophy and producing matrix metalloproteinase (MMP) and the proteinase, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), which degrades soft tissues and cartilage. [9]
  • Prostaglandins and nitric oxide (NO) produced within the inflamed synovium cause vasodilatation, resulting in swelling and pain. [10]
  • At the joint margin, the inflamed synovium (synovial pannus) releases proinflammatory cytokines, including TNF-α, IL-1, IL-6, IL-15, IL-17, IL-18, which erode cartilage and bone. [11] Additionally, bone erosions are further exacerbated by osteoclast activation, which is stimulated by the production of macrophage colony-stimulating factor (M-CSF) by synovial cells and receptor activator of nuclear factor kappa B ligand (RANKL) by activated T cells. [12]
  • IL-6 and TNF-α synergistically increase vascular endothelial growth factor (VEGF) levels, which in turn stimulate new blood vessel formation (angiogenesis), thereby maintaining pannus formation. [13] Within these blood vessels, proinflammatory cytokines activate endothelial cells, which support recruitment of leucocytes to perpetuate the inflammatory process. [14]
  • Muscles adjacent to inflamed joints atrophy and may be infiltrated with lymphocytes, leading to progressive biomechanical dysfunction that further amplifies tissue destruction. [15]

Signs of RA

Initial presentation:

  • Pain, swelling and warmth in one or more peripheral joints, often with symmetric small joint involvement. The most common joints involved include metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, and metatarsophalangeal (MTP) joints, as well as wrists. Other affected joints may include elbows, shoulders, hips, knees, and ankles. [17]
  • Patients commonly experience >1 hour of morning stiffness in affected joints. [18]
  • Constitutional symptoms such as fatigue, malaise, low-grade fever, and weight loss may occur over a period of weeks to months. [19]

Chronic presentation:

  • Fatigue is prevalent, affecting between 40% to 70% of RA patients. [20]
  • Deformities include ‘Swan-neck’ (distal interphalangeal [DIP] flexion and PIP hyperextension), ‘boutonniere’ (DIP hyperextension and PIP flexion), and ‘Z-thumb’ (MCP flexion and IP hyperextension) deformities (Figure 2). [21]
  • Ulnar deviation and subluxation of the MCP joints, as well as radial deviation of the wrists. [22]
  • Inflammation of sacroiliac and vertebral joints (cervical 1 [C1] and C2 vertebrae), leading to erosion of the odontoid peg and cervical spine misalignment. [23]
  • Joint damage involving the wrists, elbows, shoulders, hips, and knees, which can lead to severe osteoarthritis, necessitating joint surgery and/or replacement. [24]

Extra-articular manifestations [26]:

Systemic

  • Fever
  • Weight loss
  • Fatigue
  • Susceptibility to infection

Musculoskeletal

  • Muscle-wasting
  • Tenosynovitis
  • Bursitis
  • Osteoporosis

Haematological

  • Anaemia
  • Thrombocytosis
  • Eosinophilia

Lymphatic

  • Felty’s syndrome [*]
  • Splenomegaly

Nodules

  • Sinuses
  • Fistulae

Ocular

  • Episcleritis
  • Scleritis
  • Scleromalacia
  • Keratoconjunctivitis sicca

Vasculitis

  • Digital arteritis
  • Ulcers
  • Pyoderma gangrenosum
  • Mononeuritis multiplex
  • Visceral arteritis

Cardiac

  • Pericarditis (most common)
  • Myocarditis
  • Endocarditis
  • Conduction defects
  • Coronary vasculitis
  • Granulomatous aortitis

Pulmonary

  • Nodules
  • Pleural effusions
  • Pulmonary fibrosis
  • Obliterative bronchiolitis
  • Caplan's syndrome
  • Bronchiectasis
  • Pneumothorax

Neurological

  • Cervical cord compression
  • Compression neuropathies
  • Peripheral neuropathy
  • Mononeuritis multiplex

Key Drivers:


  • Infectious agents: Infectious triggers are proposed to invoke autoimmunity by causing cross-reactivity between proteins expressed by the pathogen and the host (molecular mimicry). Additionally, infectious agents stimulate the release of sequestered antigens (previously not visible to the immune system) from tissues that have been damaged during infection, as well as stimulating the production of inflammatory cytokines that overwhelm the normal control mechanisms that prevent bystander damage. [27]Porphyromonas gingivalis infection and untreated periodontal disease in patients with a genetic predisposition for RA is strongly associated with RA pathogenesis. [28] P. gingivalis has been shown to citrullinate peptides in the oral mucosa, promoting ACPA generation via peptidylarginine deaminase enzyme (PAD) activity, [29],[30],[31] and has an affinity for HLA-DR4. [32] P. gingivalis is also proposed to alter immune function by forming immune complexes, causing phagocyte activation [33] and locally targeting toll-like receptor 2 (TLR2). [34] This process promotes inflammatory cytokine production, altering the function of T helper 17 (Th17) cells. [35] Additionally, P. gingivalis infection has been shown to stimulate and progress disease activity in patients already diagnosed with RA. [36] Other infections associated with RA development include Epstein-Barr virus (EBV) and Herpes simplex viruses (HSV). [37]
  • Environmental risk factors: Environmental triggers are proposed to alter gene expression and disturb immune homeostasis. Exposure to tobacco is strongly associated with RA development in genetically susceptible people, accounting for 20% to 30% of the environmental risk for RA, [38] and is associated with more severe disease and reduced responsiveness to treatment. [39] Smoking is most strongly associated with ACPA-positive RA, increasing the citrullination of proteins and the subsequent generation of ACPA. Additionally, smoking is associated with increased periodontal disease and lung disease, and may therefore contribute to inflammation and autoimmunity at these sites. [40] Beyond tobacco exposure, multiple studies have consistently demonstrated an association between exposure to occupational silica and RA, in particular ACPA-positive RA. Additionally, increased exposure to inhaled particulate air pollution is associated with increased risk for RA. [41]
  • Microbiome disruptions: Diverse gut microbiota provide multiple immunologic activities through their interactions with the intestinal epithelia and mucosal immune response, with which the microbiome builds a complex barrier against intestinal pathogenic bacteria. The microbiota ensures the integrity of the gut barrier by releasing antibacterial molecules (bacteriocins) and anti-inflammatory short-chain fatty acids, or by activating essential cell receptors for the immune response. Alterations in diversity or functional changes of the intestinal microbiota (dysbiosis) alters the immune response, increases epithelial permeability and destabilises intestinal homeostasis, therefore compromising immunity and perpetuating autoimmunity. [42] In addition, commensal bacteria help to shape the immune response by inducing specific T regulatory cells (Tregs) within the intestine. Eradication of the normal flora with broad-spectrum antibiotics commonly results in opportunistic infection by organisms such as Clostridium difficile, which rapidly colonise an undefended ecological terrain. [43]
  • Cell danger response (CDR) dysfunction: The mitochondria are involved in cellular healing processes, known as the cell danger response (CDR). Progression through the CDR enables recovery from a stressor and avoidance of chronic disease, however in infection-associated conditions, pathological mitochondria cause dysfunction within the CDR cycle, resulting in impaired/incomplete cellular healing processes.[44] The three sequential phases/checkpoints that form the CDR include:
    • CDR1: Innate immunity stimulates proinflammatory reactive oxygen species (ROS) to prevent/neutralise pathogenic infection. Cell communication to neighbouring cells is disrupted to prevent infectious spread.[45]
    • CDR2: Increased proliferation involving stem cells and genetic material to rebuild tissue lost during CDR1.[46]
    • CDR3: Cellular energy and resources are used to differentiate the new cells into their specialised roles, and cellular communication is restored.[47]

If the CDR is blocked at any checkpoint, the innate immunity, proliferation or differentiation phases are left ‘switched on’, causing them to become pathogenic and a trigger of fatigue and infectious/chronic illness.[48] For example, autoimmune disease patients, despite potentially having any number of triggers, share a common profile of a prolonged CDR3 state.[49]

  • Hormonal influence: The increased prevalence of RA in women suggests that female hormonal factors play a role in the development of the disease, with women accounting for approximately two-thirds of individuals who develop RA. [50] The mechanism underlying hormonal influence and RA pathogenesis remains unclear, however the effect of sex hormones on the immune system and their interaction with environmental and genetic factors may explain the higher prevalence of RA in women. [51] Hormone-driven conditions that are associated with increased risk for RA include early menopause and polycystic ovarian syndrome. Additionally, RA cases are significantly more frequent in the 24 months after birth, while pregnancy has been found to be protective, both for RA development and for activity in already established disease. Long-term breastfeeding, hormone replacement therapy and oral contraceptives (combined oestrogen and progesterone) have been consistently found to decrease the risk of RA. [52]
  • Chronic stress: Chronic stress alters the HPA axis response to promote excessive release of proinflammatory cytokines, therefore altering the immune response and increasing the susceptibility to immune dysfunction and infectious development. Chronic secretion of catecholamines, noradrenaline, adrenaline, and dopamine, enhance the growth of pathogens,[53] while also lowering natural killer (NK) cell activity, which increases vulnerability and incidence of infectious disease.[54]
  • Dietary factors: Lower intake of vitamin D and antioxidants, as well as higher intake of sugar, sodium, red meats, protein, and iron have been associated with RA development. Conversely, a higher intake of fish and omega-3 essential fatty acids (EFAs), leading to higher serum levels of fatty acids, have been consistently linked to decreased risk for RA. [55]
  • Poor sleep quality: Sleep dysregulation is associated with increased CRP and IL-6, reduced NK cell activity and cytotoxicity, lowered neutrophil phagocytosis, increased superoxide production, and diminished CD4+ T cell levels.[56],[57] These factors compromise the immune system and may lead to the development of critical and chronic infections, as well as exacerbating chronic inflammation.
  • Genetic susceptibility: The HLA gene complex codes for cell surface proteins, known as major histocompatibility complex (MHC), which are involved in pathogen recognition and elimination by the immune system. [58] HLA genes are highly polymorphic, with many HLA variants including alleles and haplotypes (combinations of alleles that frequently occur together). Specific HLA variants have been associated with risk of infectious disease, as well as RA development, affecting susceptibility and pathogen clearance. Specifically, these variants can impair antibody response, altering the way that antigens are presented to T cells for immune recognition and allowing them to recirculate and trigger an aberrant inflammatory response. [59]

Red Flags:

  • Cardiovascular disease (CVD): CVD is markedly increased in RA patients due to accelerated atherosclerosis from chronic inflammation. Traditional cardiovascular risk factors such as hypertension, hyperlipidemia, smoking, diabetes mellitus and physical inactivity are also highly prevalent among patients with RA, further contributing to the CVD risk. [ 60] Adequate control of RA disease activity as well as management of CVD risk factors are needed to mitigate the heightened CVD risk. Refer to the Cardiovascular Disease Protocol for treatment guidelines. Screen patient for cardiovascular signs and symptoms using the Cardiovascular Risk Assessment Questionnaire, monitor blood pressure and refer patient for pathology testing, including homocysteine, ESR, hs-CRP, lipid profile, and blood glucose. Refer patient to a General Practitioner for assessment if CVD is suspected.
  • RA-associated lung disease: There are a variety of pulmonary manifestations of RA, including pulmonary parenchymal disease (interstitial lung disease) and inflammation of the pleura (pleural thickening and effusions), airways, and pulmonary vasculature (vasculitis and pulmonary hypertension). These changes may reflect chronic immune activation associated with RA, increased susceptibility to respiratory infection (often related to immunomodulatory medications) or occur secondary to immune-modulating medications (drug toxicity) used to treat RA. [61] If patient presents with respiratory symptoms, refer to a General Practitioner for pulmonary function assessment.
  • Recurrent or serious infection: RA patients are twice as likely to develop serious infections such as Mycobacteria species (spp.), Staphylococcus aureus, Listeria monocytogenes, Varicella zoster virus and Leishmania spp. compared to the average population. [62] In addition to having increased susceptibility to common community-acquired pathogens, immunocompromised patients are vulnerable to opportunistic pathogens, including Cryptococcus, Candida and Aspergillus species, as well as the reactivation of endogenous but latent organisms such as Herpes viruses, Toxoplasma gondii and Pneumocystis jiroveci. [63] Recurrent infections are also more common, with infection risk increasing almost three-fold for those with mild RA and nearly five-fold for those with severe RA. [ 64] Age, surgery and immunosupressive medications are also risk factors for recurrent infections. [65] Refer patient to a General Practitioner for assessment where indicated, including bacterial/fungal cultures, viral/bacterial antibodies, WCC, and inflammatory markers (ESR and hs-CRP).

Treatment Recommendations

Core Recommendations

BCM-95™ Turmeric & Devil's Claw to Treat Chronic Inflammation

Dosage: Acute dose: 3 capsules twice daily, reducing to the maintenance dose of 1 capsule morning and two capsules evening, once symptoms have improved.

A combination of herbs to reduce the production of inflammatory mediators at multiple points of the inflammatory cascade, while also decreasing oxidative stress and tissue damage, and reducing RA disease activity.

Mechanism of Action/Clinical Research:

  • Curcumin has broad anti-inflammatory effects, decreasing many inflammatory mediators including phospholipase, lipoxygenase (LOX), cyclooxygenase–2 (COX-2), leukotrienes (LTs), thromboxane, prostaglandins (PGs), NO, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1, interferon-inducible protein, TNF-α, and IL-12. [66],[67]
    • Forty-five patients were randomised into three equal groups to receive either BCM-95™ Turmeric (25 g/d), diclofenac sodium (50 mg/d), or a combination of both. BCM-95™ Turmeric was found to be as effective or superior to diclofenac sodium for reducing RA symptoms. [68]
  • Curcumin has been shown to inhibit the production of MMP-3, MMP-9 [69] and MMP-13 while also restoring type-2 collagen and glycosaminoglycan synthesis in human chondrocytes, thereby reducing tissue damage associated with chronic infection/inflammation. [7 0]
  • Boswellic acid, acetyl-11-keto-beta-boswellic acid (AKBA), demonstrates anti-inflammatory actions via allosteric regulation of 5-LOX, resulting in LT inhibition. [71] Additionally, boswellia exerts anti-inflammatory activity further up the inflammatory cascade, inhibiting the activation of proinflammatory signalling pathway, nuclear factor kappa B (NFĸB). [72]
  • Devil’s claw provides significant analgesic effects by reducing pain sensations in the brain via increasing gamma-aminobutyric acid (GABA) levels and opioid activity, while also reducing glutamate signalling. [73]
    • An eight-week study involving 259 arthritis patients who were prescribed 1.4 g/d to 2.9 g/d of devil’s claw for eight weeks reported a significant reduction in pain, stiffness and function, as well as an increase in quality of life. Forty percent of participants also recorded significant improvements in pain, daily functioning and stiffness after just two weeks of treatment. [74]

Specialised Pro-Resolving Mediators [†]

Specialised pro-resolving mediators (SPMs) to promote the resolution of underlying systemic inflammation, which is associated with progressive joint disease and immune dysregulation.

Mechanism of Action/Clinical Research:

  • SPMs encourage resolution by regulating macrophage polarisation. SPMs trigger the switch from proinflammatory M1 macrophages to anti-inflammatory M2 macrophages, reducing inflammation and tissue damage, and promoting resolution. Additionally, M2 macrophages have been shown to inhibit polymorphonuclear neutrophils (PMNs) and promote efferocytosis and tissue repair.[75]


Highly Bioavailable PEA and Magnesium for Neuromuscular Support and Pain

Dosage: Add 1 level scoop (5 g) to 200 mL of water twice daily, with food.

A combination of PEA* and Magnesium bisglycinate with anti-inflammatory, glutamate-blocking and endocannabinoid-like actions to attenuate pain signaling associated with RA joint pain and functional limitations.

Mechanism of Action/Clinical Research:

  • Magnesium has been found to block glutamate via inhibition of the N-methyl-D-aspartate (NMDA) receptor and reduce excitatory neurotransmission associated with pain signalling and increased pain sensitisation.[76]
  • Through enhancing endogenous cannabinoid system (ECS) activity, PEA reduces pain amplification driven by immune cells (i.e. microglial and astrocytes), [77],[78] and helps to downregulate TRPV1 nociceptor sensitivity. [79],[80]
  • In patients with chronic neuromuscular joint pain, one week of 900 mg/d of PEA followed another a second week of 600 mg/d of PEA decreased pain intensity scores (from 69.9% down to 7.6%) compared to ibuprofen (reduced from 68.4% down to 37.4%; p<0.0001). [81]

Highly Bioavailable Palmitoylethanolamide (PEA) with Endocannabinoid Action

Dosage: Take 1 capsule twice daily.

Highly bioavailable Palmitoylethanolamide (PEA)*, providing endocannabinoid-like actions to support pain relief, including nerve pain, while also providing neuroprotection and anti-inflammatory assistance to RA patients.

Mechanism of Action/Clinical Research:

  • PEA is an endocannabinoid-like lipid mediator influencing a variety of receptors and immune cells to provide anti-neuroinflammatory, analgesic and neuroprotective actions. PEA is endogenously produced in the body, with levels declining during chronic disease, tissue damage, inflammation, pain syndromes and ageing. [82]
  • PEA has an association with the ECS and key bioactive endocannabinoids, anandamide (AEA) and 2- arachidonoylglycerol (2-AG). [83] The ECS regulates an array of physiological functions in the body, [84] with imbalances contributing to the development of several psychological and neurodegenerative disorders. [85],[86],[87]
  • PEA supports the ECS via directly modulating endocannabinoid signalling (via receptor expression of peroxisome proliferator-activated receptors [PPARs] or orphan G protein-coupled receptor [GPR55] or G protein-coupled receptors [GPCR]) and indirectly activating transient receptor potential vanilloid receptor type 1 (TRPV1) and cannabinoid receptors (CB1, CB2). [88],[89],[90]

High Purity, Low Reflux, Concentrated Fish Oil Liquid or Capsules

Dosage: 4.2 mL (1 tsp) daily or 2 capsules twice daily.

Omega-3 EFAs to reduce the production of inflammatory cytokines, MMPs and VEGF, which degrade soft tissue and cartilage and perpetuate RA inflammation.

Mechanism of Action/Clinical Research:

  • Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) modulate the production of eicosanoids, cytokines and other factors such as PPARs, which regulate the inflammatory response.[91],[92],[93]
  • EPA and DHA can inhibit cytokine-induced endothelial activation and reduce endothelial migration and proliferation, essential to vascular endothelial cell wound repair. This action occurs via regulation of VEGF.[94]
  • EPA and DHA decreases proinflammatory MMP-9, a protease that regulates pathological remodelling of the extracellular matrix, basement membrane, and other tissues in the body by digesting collagen components in these tissues, causing inflammation and fibrosis.[95]

Lactobacillus paracasei LP-33 ® and Lactobacillus rhamnosus (LGG ®) for Immune Control

Dosage: 1 capsule daily.

Clinically trialled probiotic strains to restore immune control and moderate over-active immune responses associated with RA pathogenesis.

Mechanism of Action/Clinical Research:

  • Lactobacillus paracasei LP-33 ® and Lactobacillus rhamnosus (LGG ®) have been shown to induce Treg cell production, which provides immunoregulatory support (Th1 and Th2 cytokine balance) and dampens inflammation in immune disorders. [96],[97]
  • Lactobacillus rhamnosus (LGG ®) has the capacity to induce IL-10, a key anti-inflammatory and immunoregulatory cytokine that is expressed by Tregs and Th2 cells. [98]

Additional Considerations

Support joint repair:

Gelatin Complete Joint Restore Powder

Dosage: Add 1 level scoop (15 g) once daily, to 200 mL of water or as directed by your healthcare professional.

Gelatin, glucosamine, methylsulfonylmethane (MSM) and synergistic nutritional cofactors to assist in the regeneration of articular cartilage and reduce chronic tissue inflammation, thereby helping to limit the effects of joint degeneration.

Mechanism of Action/Clinical Research:

  • Gelatin has been shown to increase the biosynthesis of type II collagen[99] required for cartilage repair and arthritis treatment.[100] Gelatin has been found to increase plasma levels of collagen,[101] with human studies indicating a two-fold increase in collagen levels within an hour of gelatin ingestion.[102]
  • MSM is an organic form of sulphur required for the formation of connective tissue.[103] MSM counters inflammation and oxidative stress at the transcriptional and subcellular level,[104] including inhibition of NFκB, resulting in the down-regulation of inflammatory cytokines (IL-1, IL-6 and TNF-α); reducing local tissue inflammation.[105]
  • Beyond rebuilding cartilage (via biosynthesis of proteoglycans and glycosaminoglycans [GAGs] within cartilage), glucosamine also supports cartilage retention by inhibiting hyaluronidase enzymes implicated in cartilage degradation, supporting the lubricant properties of synovial fluid.[106]
  • Silica plays a key role in the formation and maintenance of bone and cartilage and is involved in both collagen and GAG formation within the extracellular matrix.[107]
  • Boron has been shown to support the production of extracellular matrix components, integral to connective tissue.[108]
  • Vitamin K dependent proteins, including gamma-carboxyglutamic acid-rich protein and unique cartilage matrix-associated protein, reduce the calcification of soft tissue implicated in degenerative joint disease.[109]
  • Vitamin D binds to its receptors, triggering a cascade of cellular activity that leads to chondrocyte hypertrophy, promoting extracellular matrix production and the regeneration of articular cartilage.[110]


If vitamin D levels are <100 nmol/L:

Vitamin D3

Dosage: Take 1 capsule daily with food.

Vitamin D to modulate the innate and adaptive immune responses, supporting immune function during autoimmunity and infection.

Mechanism of Action/Clinical Research:

  • It is well known that vitamin D plays an important role in regulating immune function, with deficiency impacting the activity of Tregs, [111],[112] as well as the production of antibodies and regulation of dendritic cell function. [113]
  • Vitamin D enhances the adaptive immune response by increasing the differentiation of monocytes to macrophages and stimulating white blood cell proliferation, essential to the neutralisation of viral infections. [114]
  • With receptors expressed on a wide variety of cell types, vitamin D is involved in the modulation of activated T and B lymphocytes. [115]
  • Vitamin D has been shown to regulate T helper cell function. [116]

If patient presents with signs of infection:

High Bioavailability Zinc with Vitamin C

Dosage: Children 4 to 8 years: Acute: Add ¼ metric teaspoon (0.95 g) to 100 mL water once daily with food; Children 9 to 13 years: Acute: Add ¼ metric teaspoon (0.95 g) to 100 mL water twice daily with food; Children 9 to 13 years: Maintenance: Add ¼ metric teaspoon (0.95 g) to 100 mL water once daily with food. Adults and children over 14 years: Acute: Add ½ metric teaspoon (1.9 g) to 200 mL water twice daily with food; Adults and children over 14 years: Maintenance: Add ½ metric teaspoon (1.9 g) to 200 mL water once daily with food.

Zinc and vitamin C to support the development, function and mediation of immune cells, thereby reducing infectious susceptibility, while also supporting biochemical and cellular reactions required for tissue repair and remodeling.

Mechanism of Action/Clinical Research:

  • Vitamin C supplementation has been shown to reduce the duration and severity of infections [117] and is increasingly efficacious when combined with zinc, with deficiencies of vitamin C and zinc both severely suppressing immune responses.[118]
  • Vitamin C stimulates white blood cell production and function, enhances NK cell activity and chemotaxis, supports clearance of spent neutrophils from sites of infection, increases serum levels of antibodies, and augments lymphocyte differentiation and proliferation, facilitating innate and adaptive immune responses.[119]
  • Zinc is involved in several aspects of immunological function, including the development, function and mediation of immune cells, such as neutrophils, monocytes and NK cells. Zinc also affects the development of acquired immunity and T lymphocyte function.[120]
  • Vitamin C supports tissue repair, stimulating neutrophil apoptosis and clearance during the inflammatory phase of healing while also enhancing collagen synthesis, maturation (tissue remodelling), secretion and degradation during the proliferative phase (tissue growth).[121] Additionally, zinc is integral for restoring tissue architecture following injury, enhancing membrane repair, coagulation, tissue re-epithelialization, angiogenesis, and fibrosis/scar formation.[122]

Cordyceps, Coriolus and Reishi for Immune Stimulation

Dosage: Add 1 level metric teaspoon (2.7 g) to 125 mL of water daily.

Medicinal mushrooms to stimulate cellular and humoral immunity, providing antiviral actions while increasing resistance to virulent infections and preventing infectious reoccurrence.

Mechanism of Action/Clinical Research:

  • Cordyceps, coriolus, reishi and shiitake activate the innate immune system, triggering the production of NK cells, lymphocytes, neutrophils, macrophages, and inflammatory cytokines.[123] Cytokine synthesis prompts adaptive immune processes to take effect, through the promotion of B cells for antibody production, and stimulation of T cells, which mediate cellular and humoral immunity.[124]
  • Cordycepin, from cordyceps, stimulates host defence mechanisms such as macrophage and phagocytic activity, and up-regulates TNF-α, IL-6, IL-10, IL-12 and inducible nitric oxide synthase (iNOS), involved in the cellular immune response.[125]
  • Coriolus’ active constituent, polysaccharide krestin (PSK), stimulates cytokine production including TNF-α, IL-1β and IL-12.[126] Additionally, polysaccharides present within coriolus exhibit immune-enhancing properties such as phagocytic stimulation and promotion of NO release, whilst also increasing cytokine and chemokine production in macrophages.[127]
  • Reishi contains more than 150 biologically active polysaccharides that provide immune-enhancing, antiviral and antibacterial effects. Additionally, Ganoderma lucidum proteoglycans (GLPGs) have been found to enhance immune surveillance.[128]
  • Shiitake’s active constituent, lentinan, enhances host defence mechanisms by increasing TNF-α, IL-1, IL-3 and interferon, which promote immune cell development and differentiation. Lentinan also enhances T helper cell activity, leading to the restoration of humoral immune responses.[129] The engulfing activity of macrophages has also been shown to increase in the presence of lentinan, prompting them to seek out pathogenic threats.[130]

Lactobacillus plantarum HEAL9, Lactobacillus paracasei 8700:2 and Lactobacillus rhamnosus LGG ® to Boost Immunity

Dosage: Take 1 capsule daily.

Strain specific probiotics, with proven human health benefits, to boost and regulate immunity.

Mechanism of Action/Clinical Research:

  • Studies have demonstrated Lactobacillus plantarum (HEAL9), Lactobacillus paracasei (8700:2) and LGG®all have the capacity to induce IL-10, a key anti-inflammatory and immunoregulatory cytokine, which is expressed by Tregs and Th2 cells.[131]
    • A randomised, parallel, double-blind, placebo-controlled study involving 272 subjects supplemented with either 500 million CFU each of HEAL9 and 8700:2 or placebo for 12 weeks demonstrated a 28% reduction in the duration of the common cold and a reduction in total symptom scores by 24%.[132]
  • LGG® has been shown to protect against viral infection, including influenza, by stimulating respiratory NK cell activity, and up-regulating antiviral IFN-γ.[133],[134]
  • L. plantarum (HEAL9) and L. paracasei (8700:2) have been shown to stimulate the innate immune responses.[135]

Diet and Lifestyle Recommendations

Diet:

  • Dietary patterns high in refined starches, sugar, and saturated and trans-fatty acids, poor in natural antioxidants and fibre from fruits, vegetables, and wholegrains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines.[136]
  • Specifically, diets that contain high intakes of sugar, sodium, red meats, protein, and iron have been associated with RA development.[137] Therefore, RA patient are recommended to moderate the consumption of these foods.
  • A higher intake of fish and omega-3 EFAs, leading to higher serum levels of fatty acids, are associated with a decreased risk for RA.[138] Increased intake of EFA-rich foods is advisable.
  • Current evidence suggests that the Mediterranean diet provides protection against several diseases associated with inflammation and immune activation.[139] The Mediterranean diet has also been found to improve disease-related fatigue by lowering the inflammatory load and simultaneously balancing gut microbiota.[140]
  • The Mediterranean diet is inclusive of high intake of fruits and vegetables, lean protein, quality essential fatty acids, and wholegrains (limiting starchy grains and vegetables).
  • The Metagenics Wellness Diet reflects the wholefood principles of the Mediterranean diet and provides a simple guide to moderate portion size and the overall balance of macronutrients.
  • Increase intake of microbiome-enhancing foods to nourish commensal gut flora and enhance gut-associated immunity. Refer to the Metagenics Microbiome Enhancing Foods list for dietary recommendations.

Lifestyle:

  • Smoking cessation is advisable, as continued smoking has been associated with reduced responsiveness to treatment and poorer treatment outcomes.[141]
  • Ensure adequate sleep, achieving approximately eight hours of sleep each night.[142]
  • Avoid alcohol, illicit drugs or additional stimulant substances (caffeine, nicotine), as these may negatively impact HPA axis activity and nervous system function, contributing to daytime fatigue and/or disturbing normal sleep patterns.[143]
  • Engage in regular physical activity to improve fitness, health and wellbeing, and reduce stress.[144]
  • Epidemiological evidence indicates that regular physical activity and frequent structured exercise reduces the incidence of many chronic diseases, including communicable diseases such as viral and bacterial infections, as well as non-communicable diseases such as chronic inflammatory disorders. Regular physical activity and frequent exercise have been found to enhance immune competency and regulation, with preliminary evidence suggesting that it may also delay immunological ageing.[145]

Clinical Assessment


Clinical Screening

Rationale

Health Appraisal Questionnaire (HAQ)

The HAQ provides a comprehensive assessment of physical health, allowing Practitioners to gain insight into patient symptoms and evaluate overall health and wellbeing.

Cardiovascular Risk Assessment

A questionnaire designed to help Practitioners identify cardiovascular disease risk in patients, while also increasing patient awareness of cardiovascular signs and symptoms.

Footnote

*For formulations containing Palmitoylethanolamide (PEA) - This medicine is not to be used for more than 21 consecutive days, and may interact with other prescription analgesic medicines.

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