INGREDIENTS & RESEARCH

Arthritis

WHAT IS ARTHRITIS?

Arthritis is the swelling or inflammation of the joints and the surrounding tissues. Some common body parts which arthritis affects are the knees, fingers, wrists, toes, and hips (1,7). Arthritis results in severe joint pain which impedes on one’s quality of life by affecting their ability to complete basic tasks (2).  In fact, it is identified as one of the leading causes of work disability in the U.S. and is a chronic condition in the country (3).

The prevalence of arthritis is high and is continuously increasing, especially in adults with comorbidities such as obesity, diabetes and heart disease (3). Comorbidity refers to multiple diseases, illnesses or chronic conditions present in a person simultaneously (5,6).

Arthritis is grouped into three main categories: (24)

  1. Septic (or infective) arthritis is an infection but is also differentiated and identified as an inflammatory disease affecting the joints. It is generally considered a secondary infection because it is of a result of a bacterium which escapes from the bloodstream and contaminates surrounding tissues. The most frequent causative organism is Staphylococcus aureus. Other causative agents include Streptococci from groups A, B, C and G, Streptococcus pneumoniae, Escherichia coli, Proteus sp., Salmonella sp., Serratia marcescens, Neisseria sp. Speed and accuracy of treatment is often required to avoid irreversible joint destruction which contributes to extensive morbidity and mortality (25,26).
  1. Reactive arthritis is also known as postinfectious arthritis and is characterized by inflammation of the tissues and joints occurring post gastrointestinal or genitourinary infections. It occurs approximately four weeks post an acute diarrheal illness (17,27,28,29,33).
  1. Inflammatory arthritis. Historically, pain is identified as the main reason why patients with inflammatory arthritis seek the expertise of a rheumatologist. One of the main contributors to pain in inflammatory arthritis is peripheral inflammation (31,32).

The most common types of inflammatory arthritis are osteoarthritis and rheumatoid arthritis: (3,8)

  • Osteoarthritis- the clinical syndrome of joint pain coupled with varying degrees of functional limitation and reduced quality of life. It is the most common form of arthritis. It occurs when the equilibrium between the breakdown and repair of joint tissue is interrupted. Osteoarthritis is characterized pathologically by the loss of cartilage, transformation of adjacent bone as well as accompanying inflammation. In contrast to the widespread belief, osteoarthritis is not caused by aging and it does not guarantee deterioration. It affects peripheral joints such as hips, knees and small hand joints (12,36,38).
  • Rheumatoid arthritis is an autoimmune disease that affects the lives of 1.3 people in U.S. Onset generally occurs between 30-50 years, mostly in adulthood and in females. It is characterized by the inflammation of the synovium and is responsible for fluid production in the joints. Synovium refers to the soft tissue which lines the spaces of diarthrodial joints, tendon sheaths and bursae and is often the pathological point of focus in several inflammatory joint diseases (13,100).

Other types of arthritis include:

  • Psoriatic arthritis- an inflammatory musculoskeletal disorder linked to psoriasis. Psoriasis is an inflammatory condition which presents scaly skin lesions frequently occurring on the knees and elbows but can sometimes affect other body parts (16).
  • Gout - the most common form of inflammatory arthritis. It manifests as an intermittent occurrence of synovitis resulting in joint swelling and pain. These occurrences are also known as acute gouty arthritis attacks or flares. Gout can also progress to develop tophi (crystals in the joints due to deposits of monosodium urate-MSU). Hyperuricemia is the main contributory factor behind episodes of gout. It is the inadequate excretion of uric acid or the overproduction of uric acid. Other factors include genetics, hormones, pharmacological and dietary factors, advancing age, and family history (19).

 

RISK FACTORS AND SYMPTOMS OF ARTHRITIS

Septic arthritis (25)

Risk factors:

  • Prior surgery
  • Alcohol and/or intravenous drug abuse
  • Diabetes mellitus
  • Leg ulcers
  • Intra-articular corticosteroid injection
  • Immunodeficiencies
  • Elderly and very young children

Symptoms:(34)

  • Hot, swollen and/or tender joints
  • Joints with a minimized range of movement

Reactive arthritis (33,35)

Risk factors:

  • Predominantly young adults between the ages of 20-40
  • Gender: males are more affected than females 3:1 respectively
  • Patients who are HLA B27 (human leukocyte antigen (HLA) class I molecule B27) positive- there is a 50% chance of developing reactive arthritis as it restricts immune responses to bacteria (102,103).

Symptoms:(33)

  • Musculoskeletal manifestations- lower limb, knees, metatarsophalangeal (MTP) joints and ankles are affected. Some patients may even experience pain in the lower back and buttocks.
  • Defects in the skin and nail
  • Ocular dysfunctions
  • Gastrointestinal involvement- acute or chronic lesions found in the large or small intestines.
  • Cardiac involvement- Proximal aortitis depending on the severity may lead to cardiac arrest or death.

Osteoarthritis: (12,37)

Risk factors:

  • Genetic factors; 40-60% hereditary, however, the exact genes are still unknown.
  • Constitutional factors- high bone density, age, female sex, obesity.
  • Biomechanical factors- joint injury, reduced muscle strength, occupational/recreational usage, joint malalignment.

Symptoms: (37)

  • Joint pain

Rheumatoid arthritis: (39)

Risk factors:

  • Genetics
  • Alterations in the female hormonal environment due to factors such as breastfeeding, pregnancy and the use of oral contraceptives
  • Smoking and/or second-hand smoking
  • Occupational hazards such as exposure to silica dust
  • Diet- excessive caffeine and red meat consumption as well as foods low in antioxidants

Symptoms: (13,40)

  • Warm, swollen and painful joints
  • Stiff joints resulting from long periods of rest
  • Muscle weakness from lack of use
  • Physical weakness and exhaustion
  • Rheumatoid nodules (small, hard lumps develop under the skin as the disease progresses)
  • Genetic susceptibility is identified as an influential factor in rheumatoid arthritis. Research shows the importance of T cells, B cells, and cytokines in the pathological process of rheumatoid arthritis.

 

ARTHRITIS FACTS AND STATISTICS

As the population ages, the prevalence of arthritis cases diagnosed increases. By 2040 it is estimated that 78.4 million adults (age 18 years and older) will suffer from the chronic symptoms that accompany arthritis.

  • Between 2013-2015, 54.4 million (1 in every 4) U.S. adults were diagnosed with arthritis. A higher age prevalence was identified in females compared to males; 23.5% to 18.1% respectively.
  • Osteoarthritis is known as the eleventh cause of disability in the world.
  • The annual incidence rate of reactive arthritis is 0.6-27 per 100,00 patient years.
  • The annual incidence of early inflammatory arthritis ranges between 115-271 per 100,000 adults (2,3,4,25,27,32).

 

MEDICAL TREATMENT OF ARTHRITIS

  1. Acetaminophen/paracetamol has been the first line of numbing or analgesic agent since the late 19th century and general practitioners use it for spinal pain and osteoarthritis of the hip and knee (43).

Common side effects:(43,53)

  • High doses of paracetamol can result in hepatotoxicity (drug-induced liver damage) (104).
  • Increased blood pressure in ambulatory patients with coronary artery disease (even from licensed doses)
  1. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used and known for their effectiveness as anti-inflammatory and numbing agents. They inhibit the production of prostaglandins by hindering any activity of cyclooxygenase enzymes. Prostaglandins are lipid autacoids that play a major role in the production of an inflammatory response (41,42).

Common side effects include esophagitis, stomach ulcers, weight gain and edema, sodium retention, acute renal failure, and hypertension.

  1. Conventional Opioids are the oldest analgesic agents, drugs or treatment used to manage or relieve pain (107) and are commonly prescribed to patients with arthritis-related pain. However, guidelines established by the CDC indicate that there is insufficient evidence to support the use of such drugs and long-term usage is hazardous for patients.

If NSAIDs or paracetamol are unable to alleviate the pain caused by arthritis, then opioids may be considered after risk assessment (especially in elderly people) (3,41).

Common side effects include sedation, dizziness, nausea, vomiting, constipation, and addiction (10).

 

NATURAL WAYS TO SUPPORT HEALTHY LUNGS

Practices to Support Healthy Joints:

Exercise therapy- lessens pain and improves function by approximately 40%. Physical activity is cost-saving in the long run because it reduces annual healthcare cost. An analysis of arthritis patients enrolled in a fitness program (as an evidence-based physical activity intervention) revealed that each person’s healthcare cost was reduced by $945 (3).

Cognitive Behavioral Therapy (CBT)- studies reveal that a combination of tailored CBT and exercise training in high-risk patients with fibromyalgia improves long-term physical and psychological functioning. Similarly, it is also seen as effective in patients at risk in the early stages of rheumatoid arthritis and osteoarthritis (45,46,47).

Natural Supplements That Help Support Healthy Joints:

 

REFERENCES

  1. Arthritis - National Library of Medicine - PubMed Health. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024677/. Accessed April 17, 2018.
  2. Living with Severe Joint Pain | Features | CDC. https://www.cdc.gov/features/arthritis-quality-life/index.html. Accessed April 17, 2018.
  3. Barbour KE, Helmick CG, Boring M, Brady TJ. Vital Signs: Prevalence of Doctor-Diagnosed Arthritis and Arthritis-Attributable Activity Limitation — United States, 2013–2015. MMWR Morb Mortal Wkly Rep. 2017;66(9):246-253. doi:10.15585/mmwr.mm6609e1
  4. Hootman JM, Helmick CG, Barbour KE, Theis KA, Boring MA. Updated Projected Prevalence of Self-Reported Doctor-Diagnosed Arthritis and Arthritis-Attributable Activity Limitation Among US Adults, 2015-2040. Arthritis Rheumatol. 2016;68(7):1582-1587. doi:10.1002/art.39692
  5. Principles of Epidemiology | Lesson 3 - Section 2. https://www.cdc.gov/ophss/csels/dsepd/ss1978/lesson3/section2.html. Accessed April 17, 2018.
  6. Theis KA, Brady TJ, Helmick CG. No One Dies of Old Age Anymore: A Coordinated Approach to Comorbidities and the Rheumatic Diseases. Arthritis Care Res (Hoboken). 2017;69(1):1-4. doi:10.1002/acr.23114
  7. Arthritis Types | Arthritis | CDC. https://www.cdc.gov/arthritis/basics/types.html. Accessed April 18, 2018.
  8. Arthritis - NHS.UK. https://www.nhs.uk/Conditions/Arthritis/. Accessed April 18, 2018.
  9. Gonzales GR, Portenoy RK. Slelection of Analgesic Therapies in Rheumatoid Arthritis The Role of Opioid Medications. https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1790060409. Accessed April 18, 2018.
  10. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 Suppl):S105-20. http://www.ncbi.nlm.nih.gov/pubmed/18443635. Accessed April 18, 2018.
  11. Ramiro S, Radner H, van der Heijde D, et al. Combination therapy for pain management in inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis). Cochrane Database Syst Rev. October 2011. doi:10.1002/14651858.CD008886.pub2
  12. National Clinical Guideline Centre Osteoarthritis Care and management in adults. https://www.ncbi.nlm.nih.gov/books/NBK248069/pdf/Bookshelf_NBK248069.pdf. Accessed April 19, 2018.
  13. Donahue KE, Dan Jonas ME, Richard Hansen MA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update Comparative Effectiveness Review Drug Therapy for Rheumatoid Arthritis in Adults: An Update. https://www.ncbi.nlm.nih.gov/books/NBK97388/pdf/Bookshelf_NBK97388.pdf. Accessed April 20, 2018.
  14. Eshed I, Hermann K-G, Zejden A, Sudoł-Szopińska I. Imaging to Differentiate the Various Forms of Seronegative Arthritis. Semin Musculoskelet Radiol. 2018;22(2):189-196. doi:10.1055/s-0038-1639467
  15. Corbett M, Soares M, Jhuti G, et al. Tumour necrosis factor-α inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation. Health Technol Assess. 2016;20(9):1-334, v-vi. doi:10.3310/hta20090
  16. Gladman DD. Recent advances in understanding and managing psoriatic arthritis. F1000Research. 2016;5:2670. doi:10.12688/f1000research.9592.1
  17. Ajene AN, Fischer Walker CL, Black RE. Enteric pathogens and reactive arthritis: a systematic review of Campylobacter, salmonella and Shigella-associated reactive arthritis. J Health Popul Nutr. 2013;31(3):299-307. http://www.ncbi.nlm.nih.gov/pubmed/24288942. Accessed April 20, 2018.
  18. Matsuoka K, Kobayashi T, Ueno F, et al. Evidence-based clinical practice guidelines for inflammatory bowel disease. J Gastroenterol. 2018;53(3):305-353. doi:10.1007/s00535-018-1439-1
  19. Newberry SJ, FitzGerald J, Maglione MA, et al. Diagnosis of Gout. Agency for Healthcare Research and Quality (US); 2016. http://www.ncbi.nlm.nih.gov/pubmed/26985540. Accessed April 22, 2018.
  20. Manning FJ, Barondess JA. Changing Health Care Systems and Rheumatic Disease. 1996;256(9):0-309. http://www.nap.edu/catalog/5472.html. Accessed May 9, 2018.
  21. Forte ML, Butler M, Andrade KE, Vincent A, Schousboe JT, Kane RL. Treatments for Fibromyalgia in Adult Subgroups. Agency for Healthcare Research and Quality (US); 2015. http://www.ncbi.nlm.nih.gov/pubmed/25719189. Accessed April 22, 2018.
  22. Voorhies RM. Cervical spondylosis: recognition, differential diagnosis, and management. Ochsner J. 2001;3(2):78-84. http://www.ncbi.nlm.nih.gov/pubmed/21765723. Accessed April 22, 2018.
  23. Michet CJ, Matteson EL. Polymyalgia rheumatica. BMJ. 2008;336(7647):765-769. doi:10.1136/bmj.39514.653588.80
  24. Mathew AJ, Ravindran V. Infections and arthritis. Best Pract Res Clin Rheumatol. 2014;28(6):935-959. doi:10.1016/j.berh.2015.04.009
  25. Ferrand J, El Samad Y, Brunschweiler B, et al. Morbimortality in adult patients with septic arthritis: a three-year hospital-based study. BMC Infect Dis. 2016;16:239. doi:10.1186/s12879-016-1540-0
  26. Colavite PM, Sartori A. Septic arthritis: immunopathogenesis, experimental models and therapy. J Venom Anim Toxins Incl Trop Dis. 2014;20:19. doi:10.1186/1678-9199-20-19
  27. Hannu T. Reactive arthritis. Best Pract Res Clin Rheumatol. 2011;25(3):347-357. doi:10.1016/j.berh.2011.01.018
  28. Carter JD. Treating reactive arthritis: insights for the clinician. Ther Adv Musculoskelet Dis. 2010;2(1):45-54. doi:10.1177/1759720X09357508
  29. Zeidler H, Hudson AP. Coinfection of Chlamydiae and other Bacteria in Reactive Arthritis and Spondyloarthritis: Need for Future Research. Microorganisms. 2016;4(3). doi:10.3390/microorganisms4030030
  30. Meier J, Sturm A. Current treatment of ulcerative colitis. World J Gastroenterol. 2011;17(27):3204-3212. doi:10.3748/wjg.v17.i27.3204
  31. Lee YC. Effect and treatment of chronic pain in inflammatory arthritis. Curr Rheumatol Rep. 2013;15(1):300. doi:10.1007/s11926-012-0300-4
  32. Hazes JMW, Luime JJ. The epidemiology of early inflammatory arthritis. Nat Rev Rheumatol. 2011;7(7):381-390. doi:10.1038/nrrheum.2011.78
  33. Hamdulay SS, Glynne SJ, Keat A. When is arthritis reactive? Postgrad Med J. 2006;82(969):446-453. doi:10.1136/pgmj.2005.044057
  34. Mathews CJ, Kingsley G, Field M, et al. Management of septic arthritis: a systematic review. Ann Rheum Dis. 2007;66(4):440-445. doi:10.1136/ard.2006.058909
  35. Thomson GT, Minenko A, Schroeder ML. Host risk factors for the development of reactive arthritis: a family study. J Rheumatol. 1993;20(8):1350-1352. http://www.ncbi.nlm.nih.gov/pubmed/8230017. Accessed April 26, 2018.
  36. Palazzo C, Nguyen C, Lefevre-Colau M-M, Rannou F, Poiraudeau S. Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med. 2016;59(3):134-138. doi:10.1016/j.rehab.2016.01.006
  37. Thompson LR, Boudreau R, Newman AB, et al. The association of osteoarthritis risk factors with localized, regional and diffuse knee pain. Osteoarthr Cartil. 2010;18(10):1244-1249. doi:10.1016/j.joca.2010.05.014
  38. Hunter DJ, McDougall JJ, Keefe FJ. The symptoms of osteoarthritis and the genesis of pain. Rheum Dis Clin North Am. 2008;34(3):623-643. doi:10.1016/j.rdc.2008.05.004
  39. Oliver JE, Silman AJ. Risk factors for the development of rheumatoid arthritis. Scand J Rheumatol. 2006;35(3):169-174. doi:10.1080/03009740600718080
  40. Palazzo C, Nguyen C, Lefevre-Colau M-M, Rannou F, Poiraudeau S. Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med. 2016;59(3):134-138. doi:10.1016/j.rehab.2016.01.006
  41. (UK) NCGC. Pharmacological management of osteoarthritis. 2014. https://www.ncbi.nlm.nih.gov/books/NBK333051/. Accessed May 2, 2018.
  42. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31(5):986-1000. doi:10.1161/ATVBAHA.110.207449
  43. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015;350:h1225. doi:10.1136/BMJ.H1225
  44. Boyapati R, Satsangi J, Ho G-T. Pathogenesis of Crohn’s disease. F1000Prime Rep. 2015;7:44. doi:10.12703/P7
  45. van Koulil S, van Lankveld W, Kraaimaat FW, et al. Tailored cognitive-behavioral therapy and exercise training for high-risk patients with fibromyalgia. Arthritis Care Res (Hoboken). 2010;62(10):1377-1385. doi:10.1002/acr.20268
  46. Evers AWM, Kraaimaat FW, van Riel PLCM, de Jong AJL. Tailored cognitive-behavioral therapy in early rheumatoid arthritis for patients at risk: a randomized controlled trial. Pain. 2002;100(1-2):141-153. http://www.ncbi.nlm.nih.gov/pubmed/12435467. Accessed May 2, 2018.
  47. Keefe FJ, Caldwell DS. Cognitive behavioral control of arthritis pain. Med Clin North Am. 1997;81(1):277-290. http://www.ncbi.nlm.nih.gov/pubmed/9012765. Accessed May 2, 2018.
  48. Upadhyay AK, Kumar K, Kumar A, Mishra HS. Tinospora cordifolia (Willd.) Hook. f. and Thoms. (Guduchi) - validation of the Ayurvedic pharmacology through experimental and clinical studies. Int J Ayurveda Res. 2010;1(2):112-121. doi:10.4103/0974-7788.64405
  49. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA. 2000;283(11):1469-1475. http://www.ncbi.nlm.nih.gov/pubmed/10732937. Accessed May 10, 2018.
  50. Cibere J, Kopec JA, Thorne A, et al. Randomized, Double-Blind, Placebo-Controlled Glucosamine Discontinuation Trial in Knee Osteoarthritis. doi:10.1002/art.20697
  51. Lopes Vaz A. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthrosis of the knee in out-patients. Curr Med Res Opin. 1982;8(3):145-149. doi:10.1185/03007998209112375
  52. Pujalte JM, Llavore EP, Ylescupidez FR. Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis. Curr Med Res Opin. 1980;7(2):110-114. doi:10.1185/03007998009112036
  53. Turtle EJ, Dear JW, Webb DJ. A systematic review of the effect of paracetamol on blood pressure in hypertensive and non-hypertensive subjects. Br J Clin Pharmacol. 2013;75(6):1396-1405. doi:10.1111/bcp.12032
  54. Qiu GX, Gao SN, Giacovelli G, Rovati L, Setnikar I. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung. 1998;48(5):469-474. http://www.ncbi.nlm.nih.gov/pubmed/9638313. Accessed May 10, 2018.
  55. Qiu GX, Gao SN, Giacovelli G, Rovati L, Setnikar I. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung. 1998;48(5):469-474. http://www.ncbi.nlm.nih.gov/pubmed/9638313. Accessed May 10, 2018.
  56. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357(9252):251-256. doi:10.1016/S0140-6736(00)03610-2Pittler MH, Ernst E.
  57. Pavelká K, Gatterová J, Olejarová M, Machacek S, Giacovelli G, Rovati LC. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002;162(18):2113-2123. http://www.ncbi.nlm.nih.gov/pubmed/12374520. Accessed May 10, 2018.
  58. Kumar G, Srivastava A, Sharma SK, Rao TD, Gupta YK. Efficacy & safety evaluation of Ayurvedic treatment (Ashwagandha powder & Sidh Makardhwaj) in rheumatoid arthritis patients: a pilot prospective study. Indian J Med Res. 2015;141(1):100-106. http://www.ncbi.nlm.nih.gov/pubmed/25857501. Accessed May 7, 2018.
  59. Ramakanth GSH, Uday Kumar C, Kishan P V, Usharani P. A randomized, double blind placebo controlled study of efficacy and tolerability of Withaina somnifera extracts in knee joint pain. J Ayurveda Integr Med. 2016;7(3):151-157. doi:10.1016/j.jaim.2016.05.003
  60. Sandhu JS, Shah B, Shenoy S, Chauhan S, Lavekar GS, Padhi MM. Effects of Withania somnifera (Ashwagandha) and Terminalia arjuna (Arjuna) on physical performance and cardiorespiratory endurance in healthy young adults. Int J Ayurveda Res. 2010;1(3):144-149. doi:10.4103/0974-7788.72485
  61. Deal CL, Schnitzer TJ, Lipstein E, et al. Treatment of arthritis with topical capsaicin: a double-blind trial. Clin Ther. 13(3):383-395. http://www.ncbi.nlm.nih.gov/pubmed/1954640. Accessed May 7, 2018.
  62. Srinivasan K. Biological Activities of Red Pepper ( Capsicum annuum ) and Its Pungent Principle Capsaicin: A Review. Crit Rev Food Sci Nutr. 2016;56(9):1488-1500. doi:10.1080/10408398.2013.772090
  63. Hebert PR, Barice EJ, Hennekens CH. Treatment of low back pain: the potential clinical and public health benefits of topical herbal remedies. J Altern Complement Med. 2014;20(4):219-220. doi:10.1089/acm.2013.0313
  64. Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth. 2011;107(4):490-502. doi:10.1093/bja/aer260
  65. Henrotin Y, Mobasheri A, Marty M. Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis? Arthritis Res Ther. 2012;14(1):201. doi:10.1186/ar3657
  66. Zeng C, Wei J, Li H, et al. Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee. Sci Rep. 2015;5:16827. doi:10.1038/srep16827
  67. Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster J-Y. Structural and Symptomatic Efficacy of Glucosamine and Chondroitin in Knee Osteoarthritis. Arch Intern Med. 2003;163(13):1514. doi:10.1001/archinte.163.13.1514
  68. Saha S, Ghosh S. Tinospora cordifolia: One plant, many roles. Anc Sci Life. 2012;31(4):151-159. doi:10.4103/0257-7941.107344
  69. Patgiri B, Umretia BL, Vaishnav PU, Prajapati PK, Shukla VJ, Ravishankar B. Anti-inflammatory activity of Guduchi Ghana (aqueous extract of Tinospora Cordifolia Miers.). Ayu. 2014;35(1):108-110. doi:10.4103/0974-8520.141958
  70. Bruyere O, Pavelka K, Rovati LC, et al. Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from two 3-year studies. Menopause. 11(2):138-143. http://www.ncbi.nlm.nih.gov/pubmed/15021442. Accessed May 10, 2018.
  71. Bradley JD, Flusser D, Katz BP, et al. A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosylmethionine (SAM) followed by oral SAM therapy in patients with knee osteoarthritis. J Rheumatol. 1994;21(5):905-911. http://www.ncbi.nlm.nih.gov/pubmed/8064733. Accessed May 10, 2018.
  72. Di Padova C. S-Adenosylmethionine in the treatment of osteoarthritis. Am J Med. 1987;83(5):60-65. doi:10.1016/0002-9343(87)90853-9
  73. Berger R, Nowak H. A new medical approach to the treatment of osteoarthritis. Report of an open phase IV study with ademetionine (Gumbaral). Am J Med. 1987;83(5A):84-88. http://www.ncbi.nlm.nih.gov/pubmed/3318446. Accessed May 10, 2018.
  74. Domljan Z, Vrhovac B, Dürrigl T, Pucar I. A double-blind trial of ademetionine vs naproxen in activated gonarthrosis. Int J Clin Pharmacol Ther Toxicol. 1989;27(7):329-333. http://www.ncbi.nlm.nih.gov/pubmed/2674027. Accessed May 10, 2018.
  75. Müller-Fassbender H. Double-blind clinical trial of S-adenosylmethionine versus ibuprofen in the treatment of osteoarthritis. Am J Med. 1987;83(5A):81-83. http://www.ncbi.nlm.nih.gov/pubmed/3318445. Accessed May 10, 2018.
  76. Vetter G. Double-blind comparative clinical trial with S-adenosylmethionine and indomethacin in the treatment of osteoarthritis. Am J Med. 1987;83(5A):78-80. http://www.ncbi.nlm.nih.gov/pubmed/3318444. Accessed May 10, 2018.
  77. Maccagno A, Di Giorgio EE, Caston OL, Sagasta CL. Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med. 1987;83(5A):72-77. http://www.ncbi.nlm.nih.gov/pubmed/3318443. Accessed May 10, 2018.
  78. Caruso I, Pietrogrande V. Italian double-blind multicenter study comparing S-adenosylmethionine, naproxen, and placebo in the treatment of degenerative joint disease. Am J Med. 1987;83(5A):66-71. http://www.ncbi.nlm.nih.gov/pubmed/3318442. Accessed May 11, 2018.
  79. di Padova C. S-adenosylmethionine in the treatment of osteoarthritis. Review of the clinical studies. Am J Med. 1987;83(5A):60-65. http://www.ncbi.nlm.nih.gov/pubmed/3318441. Accessed May 11, 2018.
  80. Glorioso S, Todesco S, Mazzi A, et al. Double-blind multicentre study of the activity of S-adenosylmethionine in hip and knee osteoarthritis. Int J Clin Pharmacol Res. 1985;5(1):39-49. http://www.ncbi.nlm.nih.gov/pubmed/3888864. Accessed May 11, 2018.
  81. MOLECULAR WEIGHT AND BIOLOGICAL EFFECTS OF HYALURONAN: EVIDENCE SHOWING THAT SMALL HYALURONAN AND FRAGMENTS ARE DIFFERENT. http://www.hagyardpharmacy.com/custdocs/Bucci 2004.pdf. Accessed May 11, 2018.
  82. Schauss AG, Stenehjem J, Park J, Endres JR, Clewell A. Effect of the Novel Low Molecular Weight Hydrolyzed Chicken Sternal Cartilage Extract, BioCell Collagen, on Improving Osteoarthritis-Related Symptoms: A Randomized, Double-Blind, Placebo-Controlled Trial. J Agric Food Chem. 2012;60(16):4096-4101. doi:10.1021/jf205295u
  83. Pullman-Mooar S, Laposata M, Lem D, et al. Alteration of the cellular fatty acid profile and the production of eicosanoids in human monocytes by gamma-linolenic acid. Arthritis Rheum. 1990;33(10):1526-1533. http://www.ncbi.nlm.nih.gov/pubmed/2171540. Accessed May 11, 2018.
  84. Leventhal LJ, Boyce EG, Zurier RB. Treatment of rheumatoid arthritis with gammalinolenic acid. Ann Intern Med. 1993;119(9):867-873. http://www.ncbi.nlm.nih.gov/pubmed/8214997. Accessed May 11, 2018.
  85. Sengupta K, Alluri K V, Satish A, et al. A double blind, randomized, placebo controlled study of the efficacy and safety of 5-Loxin® for treatment of osteoarthritis of the knee. Arthritis Res Ther. 2008;10(4):R85. doi:10.1186/ar2461
  86. Sengupta K, Krishnaraju A V, Vishal AA, et al. Comparative efficacy and tolerability of 5-Loxin and AflapinAgainst osteoarthritis of the knee: a double blind, randomized, placebo controlled clinical study. Int J Med Sci. 2010;7(6):366-377. http://www.ncbi.nlm.nih.gov/pubmed/21060724. Accessed May 11, 2018.
  87. Hesslink R, Armstrong D, Nagendran M V, Sreevatsan S, Barathur R. Cetylated fatty acids improve knee function in patients with osteoarthritis. J Rheumatol. 2002;29(8):1708-1712. http://www.ncbi.nlm.nih.gov/pubmed/12180734. Accessed May 11, 2018.
  88. Kraemer WJ, Ratamess NA, Anderson JM, et al. Effect of a cetylated fatty acid topical cream on functional mobility and quality of life of patients with osteoarthritis. J Rheumatol. 2004;31(4):767-774. http://www.ncbi.nlm.nih.gov/pubmed/15088305. Accessed May 11, 2018.
  89. Kraemer WJ, Ratamess NA, Maresh CM, et al. A Cetylated Fatty Acid Topical Cream With Menthol Reduces Pain and Improves Functional Performance in Individuals With Arthritis. J Strength Cond Res. 2005;19(2):475. doi:10.1519/R-505059.1
  90. Kraemer WJ, Ratamess NA, Maresh CM, et al. Effects of Treatment With a Cetylated Fatty Acid Topical Cream on Static Postural Stability and Plantar Pressure Distribution in Patients With Knee Osteoarthritis. J Strength Cond Res. 2005;19(1):115. doi:10.1519/5050504.1
  91. Conrozier T. [Anti-arthrosis treatments: efficacy and tolerance of chondroitin sulfates (CS 4&6)]. Presse Med. 1998;27(36):1862-1865. http://www.ncbi.nlm.nih.gov/pubmed/9856136. Accessed May 11, 2018.
  92. Mazières B, Loyau G, Menkès CJ, et al. [Chondroitin sulfate in the treatment of gonarthrosis and coxarthrosis. 5-months result of a multicenter double-blind controlled prospective study using placebo]. Rev Rhum Mal Osteoartic. 59(7-8):466-472. http://www.ncbi.nlm.nih.gov/pubmed/1485136. Accessed May 11, 2018.
  93. Leeb BF, Schweitzer H, Montag K, Smolen JS. A metaanalysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol. 2000;27(1):205-211. http://www.ncbi.nlm.nih.gov/pubmed/10648040. Accessed May 11, 2018.
  94. Uebelhart D, Thonar EJ, Delmas PD, Chantraine A, Vignon E. Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study. Osteoarthr Cartil. 1998;6 Suppl A:39-46. http://www.ncbi.nlm.nih.gov/pubmed/9743819. Accessed May 11, 2018.
  95. Bourgeois P, Chales G, Dehais J, Delcambre B, Kuntz JL, Rozenberg S. Efficacy and tolerability of chondroitin sulfate 1200 mg/day vs chondroitin sulfate 3 x 400 mg/day vs placebo. Osteoarthr Cartil. 1998;6 Suppl A:25-30. http://www.ncbi.nlm.nih.gov/pubmed/9743816. Accessed May 11, 2018.
  96. Bucsi L, Poór G. Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis. Osteoarthr Cartil. 1998;6 Suppl A:31-36. http://www.ncbi.nlm.nih.gov/pubmed/9743817. Accessed May 11, 2018.
  97. Mazieres B, Combe B, Phan Van A, Tondut J, Grynfeltt M. Chondroitin sulfate in osteoarthritis of the knee: a prospective, double blind, placebo controlled multicenter clinical study. J Rheumatol. 2001;28(1):173-181. http://www.ncbi.nlm.nih.gov/pubmed/11196521. Accessed May 11, 2018.
  98. Gabay C, Medinger-Sadowski C, Gascon D, Kolo F, Finckh A. Symptomatic effects of chondroitin 4 and chondroitin 6 sulfate on hand osteoarthritis: A randomized, double-blind, placebo-controlled clinical trial at a single center. Arthritis Rheum. 2011;63(11):3383-3391. doi:10.1002/art.30574
  99. Uebelhart D, Malaise M, Marcolongo R, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthr Cartil. 2004;12(4):269-276. doi:10.1016/j.joca.2004.01.004
  100. Smith MD. The normal synovium. Open Rheumatol J.  2011;5:100-106. doi:10.2174/1874312901105010100
  101. Williams GT, Williams WJ. Granulomatous inflammation--a review. J Clin Pathol. 1983;36(7):723-733. http://www.ncbi.nlm.nih.gov/pubmed/6345591. Accessed
  102. Khan MA. Polymorphism of HLA-B27: 105 Subtypes Currently Known. Curr Rheumatol Rep. 2013;15(10):362. doi:10.1007/s11926-013-0362-y June 9, 2018.
  103. Woodrow JC, Eastmond CJ. HLA B27 and the genetics of ankylosing spondylitis. Ann Rheum Dis. 1978;37(6):504-509. http://www.ncbi.nlm.nih.gov/pubmed/107868. Accessed June 9, 2018.
  104. Björnsson ES. Hepatotoxicity by Drugs: The Most Common Implicated Agents. Int J Mol Sci. 2016;17(2):224. doi:10.3390/ijms17020224
  105. Bellato E, Marini E, Castoldi F, et al. Fibromyalgia syndrome: etiology, pathogenesis, diagnosis, and treatment. Pain Res Treat. 2012;2012:426130. doi:10.1155/2012/426130
  106. Schwarz MJ, Ackenheil M. The role of substance P in depression: therapeutic implications. Dialogues Clin Neurosci. 2002;4(1):21-29. http://www.ncbi.nlm.nih.gov/pubmed/22033776. Accessed June 11, 2018.
  107. Ortiz MI, Molina MAR, Arai Y-CP, Romanò CL. Analgesic drugs combinations in the treatment of different types of pain. Pain Res Treat. 2012;2012:612519. doi:10.1155/2012/612519