Inflammation
Rheumatoid arthritis (RA) is the commonest form of inflammatory arthritis occurring worldwide with variable incidence and severity. In Western countries one to three percent of the population is affected. The clinical presentation is heterogeneous with a wide variation in age at onset, degree of joint involvement and severity. If the disease remains active and uncontrolled the inflammation will usually spread to additional joints and gradual irreversible tissue damage will occur, causing deformity and instability of joints.
There is evidence that RA is immune mediated although it is unclear whether the disease is primarily autoimmune or initiated by an infectious agent. Chronic inflammation is believed to be initiated by T cells, which accumulate within the jointi. Vascular and synovial cell proliferation and proinflammatory cytokine production sustain chronic synovitis and contribute to the joint destructioni.
Non-steroidal anti-inflammatory drugs (NSAIDs) provide symptomatic relief in RA but do not modify the disease course and are often used in combination with disease modifying drugs (DMARDs). Many subjects taking NSAIDs experience side effectsii with gastrointestinal toxicity being the most common. This toxicity is related to cyclooxygenase (COX)-1 inhibitioniii, but efficacy is primarily related to COX-2 inhibition. COX-2 selective inhibitors have clinical efficacy similar to conventional NSAIDs and may be associated with lower incidences of complications. Corticosteroids have a possible beneficial effect on radiological progression of RA but regular use for rheumatoid synovitis is controversial due to the possible exacerbation of the osteopenia accompanying RA. Two anti-tumour necrosis factor (TNF) agents have been approved for use in RA treatment, however, long-term effects of TNF antagonists are unknowniv.
In vitro and animal studies indicate that THC and CBD have analgesic effects (through differing mechanisms)vii and anti-inflammatory effectsviii. Additionally, CBD has demonstrated anti-arthritic potential in murine collagen-induced arthritisix. The combination of analgesic and anti-inflammatory effects has a potential advantage over analgesics such as paracetamol or opioids for symptom relief in RA.
GW has explored the safety and efficacy of Sativex in a Phase II double-blind, randomised, parallel group study for the treatment of pain and stiffness caused by rheumatoid arthritis. (Blake DR et al. Rheumatology. 2006;45(1):50-2). This was the first study to use a cannabis-based medicine for treating rheumatoid arthritis and found that Sativex has a significant effect on easing pain and on suppressing the disease.
CBD has also been the focus of much anti-inflammatory research in other areas such as diabetes, atherosclerosis and eye disorders. For example degenerative retinal diseases such as uveitis are characterized by inflammation after the accumulation of reactive oxygen species (ROS). This is due to the prominent increase in infiltration of macrophages and activated microglia within the interior of the eye. Following ROS release, p38 MAPK activation is upregulated and results in an increase in TNF-alpha production. Administration of CBD blocks this oxidative mechanism decreasing TNF-alpha and therefore exerts anti-inflammatory and neuroprotective effectsx. CBD has also demonstrated the ability to increase adenosine signalling by preventing its clearance through the adenosine re-uptake transporter. Release of adenosine is an endogenous mechanism of immunosuppression evoked during cellular stress and inflammation and therefore this provides a non-cannabinoid receptor mechanism by which CBD can decrease inflammationxi. Cannabinoids also dampen cartilage destruction, and play a role in fibroblast remodeling of connective tissuesxii. THC and CBD may also benefit patients with functional rheumatological disorders, such as fibromyalgiaxiii.
References
i. Panayi GS, Lanchbury JS, Kingsley GH. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum 1992; 35 (7): 729-735.
ii. Josefson D. Cox2 inhibitors can affect the stomach lining. BMJ 1999; 319:1518.
iii. Warner TD, Giuliano F, Vojnovic I, et al. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA 1999; 96: 7563-7568.
iv. Koh ET. New disease modifying agents in adult rheumatoid arthritis. Annals of the Academy of Medicine, Singapore. 2001; 30 (2): 170-173.
v. Pertwee RG. Neuropharmacology and therapeutic potential of cannabinoids. Addiction Biology 2000; 5 (1): 37-46.
vi. Grinspoon L, Bakalar JB. Marijuana, the forbidden medicine. 1993. Yale University Press, 138.
vii. Williamson EM and Evans FJ Cannabinoids in clinical practice. Drugs 2000; 60 (6): 1303-1314
viii. Klein TW Newton CA, et al. Cannabinoids and the Immune system. Pain Res. Manag. 2001; 6 (2): 95-101.
ix. Malfait AM, Gallily R, Sumariwalla PF, et al. The non psychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci USA. 2000; 97 (17): 9561-9566.
x. Carrier EJ, Auchampach JA, Hillard CJ., Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7895-900.
xi. El-Remessy AB, Tang Y, Zhu G, Matragoon S, Khalifa Y, Liu EK, Liu JY, Hanson E, Mian S, Fatteh N, Liou GI., Neuroprotective effects of cannabidiol in endotoxin-induced uveitis: critical role of p38 MAPK activation., Mol Vis. 2008;14:2190-203. Epub 2008 Dec 3.
xii. McPartland JM. 2008. Expression of the endocannabinoid system in fibroblasts and myofascial tissues. Journal of Bodywork and Movement Therapies 12(2): 169-182.
xiii. McPartland JM. 2009. “Fibromyalgia and the endocannabinoid system,” in Fibromyalgia, 3nd Edition, by Leon Chaitow, Elsevier, Oxford, UK.