INTRODUCTION:

Arthritis is a form of joint disorder that involves inflammation of one or more joints^[1-2]. Rheumatoid arthritis (RA) is a systemic autoimmune multisystem disease characterized by joint inflammation, morning stiffness, and destruction of articular tissues and restricted joint movement^[3-5]. Arthritis can cause severe disability and ultimately affects a person's ability to carry out normal tasks, restricts the quality of life and causes premature death [6]. Any part of the body can become inflamed or painful from arthritis. Arthritis is the most common inflammatory disorders affecting approximately 0.5-1.0% of the global adult population, with female being affected three times more than males^[7-9].

RA still remains a formidable disease, producing severe crippling deformities and functional disabilities and cartilage destruction and commonly leads to significant disability, caused by no. of proinflammatory molecules released by macrophages including reactive oxygen species and eicosanoids such as, cytokines, leukotriens, prostaglandin. The regulation of these mediators secreted by macrophages and other immune cells^[10] and modulation of arachidoinic acid metabolism by inhibiting enzymes like Cox and LOX are the potential target for chronic inflammatory conditions^[11].

CLASSIFICATION OF RA^[12]

· Palindromic rheumatoid arthritis

· Juvenile rheumatoid arthritis

· Rheumatoid spondylitis

· Osteoarthritis

Osteoarthritis classified as two types

a) Primary osteoarthritis- it can occur in elderly.

b) Secondary osteoarthritis- it occurs at any stage

c) Ankylosing spondylarthritis

d) Infectious arthritis

e) Infectious arthritis

It can be classified as follows

a) Suppurative arthritis

b) Tuberculous arthritis

c) Lyme arthritis

d) Viral arthritis

e) Gout and Gout arthritis.

Epidemiology^[13]:

The prevalence of rheumatoid arthritis varies between 0.3% and 1% worldwide and is more in developed countries. It mainly affects women that man (3:1). Rheumatoid arthritis is a chronic systemic inflammatory illness with a prevalence of approximately 0.75% in India.

Pathophysiology of RA:

Although the exact cause of RA remains unknown ^[14]. Recent research suggests a genetic basis for disease development. More than 80% of patients carry the epitaph of the HLA-DRB1*04 cluster ^[15], and patients expressing two HLA-DRB1*04 alleles are at elevated risk for nodular disease, surgery related to joint destruction ^[16]. Another major risk of RA has been identified that single nucleotide polymorphism genotype across the MHC including those found on the conserved A1-D8-DR3 (8.1) haplotype and those near the HLA-DPB1 gene ^[17]. Various factors such as smoking and infection may also influence the development, rate of progression of RA ^[18-19]. Immune modulator like effector cells, cytokines and various signalling pathways are involved in the pathophysiology of RA ^[20].

Cell mediated immunity:

CD4+ cells activate B cells via CD28/CD40 cell surface receptor interactions, and macrophages will be activated via cell surface CD69 and by secreting cytokines, interleukin (IL-17). The autoantibody developed from the B cells secreting plasma cells, cytokines such as Tumor necrosis factor (TNF) α and IL-1 are released by activated macrophages. These two cytokines will attract the macrophages and neutrophils, it will alterthe vascular endothelium and influence local cells in the synovium ^[21-22].

Synovial changes:

In normal condition synovium consist of macrophage like and fibroblast like synoviocytes and these cells will form a very thin layer and produce synovial fluid. But in RA condition the fibroblast like synoviocytes are activated by the CD4+ t cells, and TNFα and IL-1, so resulting in the phenotype of the cells to alter, multiply and become hyperplastic. These cells secrete matrix metalloproteinase (MMP_s) causing cartilage and bone destruction and leading to erosions ^[23-24].

In addition to joint symptoms many patients experience extra-articular, and systemic manifestations ^[25]. Extra articular manifestation includes vasculitis, rheumatoid nodules, rheumatoid lung, uveitis, keratoconjunctivitis sicca [26], systemic manifestation include acute-phase protein production, anaemia, cardiovascular disease, osteoporosis, fatigue, depression ^[27-28].

Fig:1 Normal person hand

Fig:2 Rhematoid arthritis induced person hand

Diagnosis:

Diagnosing Rheumatoid arthritis in early stages can be difficult. The American College of Rheumatology uses this list of criteria:

1) Morning stiffness in and around the joints for at least one hour.

2) At least one swollen area in the wrist, hand, or finger joints

3) Arthritis involving the same joint on both sides of the body

4) X-ray changes in the hands and wrists typical of rheumatoid arthritis,

5) Swelling or fluid around three or more joints simultaneously.

Treatment:

The mediator released from the synovium, bone or other tissue will induce the sensitization of articular pain receptors. Treatment with systemic or topical therapies designed to reduce inflammatory mediators might be expected to have a beneficial effect.

Pharmacological therapies:

Paracetamol (acetaminophen):

This drug has been used for over 100 years but mechanism of action of this drugs still uncertain . Various action have been made about the mechanism of action of paracetamol that inhibition of central cyclooxygenase activity, and inhibition of N-methly-D-asparatate receptor activity, and the stimulation of descending inhibitory activity. Now a days Paracetamol is effective in many arthritic condition. Paracetamol is recommended as the oral analgesic drug of choice for mild to moderate pain in arthritis ^[40].

Non-steroidal anti-inflammatory drugs:

The major mechanism of action of NSAID_s is inhibitory effect on cyclooxygenase enzyme and decreasing in inflammatory prostaglandins such as PGE₂ and prostacyclin. NSAID_sare highly effective in the treatment of acute rheumatoid arthriticpain^[41]

Corticosteroids:

Corticosteroids have been used in treatment of RA since last 60 years. Corticosteroids like prednisolone, prednisone are widely used in treatment of RA. Long term treatment of corticosteroids reduces synovitis, and decrease joint damage however it develops various infections and the overall effect of corticosteroids are unfavourable. Intra articular glucocorticoids are highly effect in local treatment of individual active joints ^[42].

Disease Modifying Anti-rheumatic Drugs (DMARD_S):

Ex: Methotrexate, Leflunomide, Hydroxychloroquine, Chloroquine, cyclosporoine, sulfasalazine, gold salts.

This types of drugs does not include any specific class of drugs but is a large and heterogeneous collection of various types of drugs grouped together according to their convention and efficacy in treating the RA [43]. The mechanism of action of this class of drugs still unknown, but they reduce joint swelling and pain, decrease acute phase markers, and improve the function. Methotrexate is dominant DMARDS, Sulfasalazine and Leflunomide are widely used.

Cytotoxic drugs:

Ex; Cyclophosphamide.

This cytotoxic drugs produces cytotoxic effect on both T-cells and B-cells. It will supresses the B-lymphocyte activity. This drugs is cytotoxic to many tissues, but mainly affect the kindeys and heart. This cyclophosphamide is teratogenic and it should be avoided during breast feeding and pregnancy ^[44].

Biological therapies in Rheumatoid arthritis:

Ex: etanercept, abatecept, golimumab, anakinra, cerolizumab.

These agents for the treatment for disease the use of TNF-inhibitors, T-Cell co-stimulatory blockers, B-cells depletion, molecules, IL-1 receptor antagonist. TNF inhibitors are having increased risk for infections, fungal infection, and pancytopenia.

ANIMAL MODELS IN ARTHRITIS:

Collagen-induced arthritis in mice (CIA):

Principle:

CIA is a frequently used animal model for RA. There are three different cartilage derived proteins are responsible for induction of arthritis in rats.i.e. collagen type II, collagen type XI, and cartilage oligomeric matrix protein. To study mechanism of immunes response to auto antigen this is an excellent model. Mouse Cia shares many clinical histologic and immunologic features with human RA ^[45]. After the induction of disease there is development of both cellular and immune response to type II collagen. T cell and T cell derived cytokines promote activation of macrophages, osteoclasts and fibroblast causes of erosive arthritis . More recently protocol has been developed for the induction of CIA in nonsusceptible C57BL/6 mice which canbe used in genetically modified moue strains. In this model 2 intradermal injection of chicken type II collagen on the day of 0 and 21^st day result in the development of arthritis ^[46].

Procedure:

Type II collagen is dissolved in a 10mM (4mg/ml) acetic acid over night at 4⁰C. afterh that it is emulsified in an equal volume of chilled Complete Freund’s adjuvant and mixed for 30 mins at 1000rpm. Arthritis can be induced by the subcutaneous injection of 100µl of emulsion into plantar surface of paw. After 7 days of injection animal are boosted by the intradermal injection of emulsion into the base of tail with a same volume. Drug treatment to standard and test group started from the 18^th day after chronic infection of disease continued till 36^th day. The both hind paw volume is measured by plethysmmographically^[47]

Complete Freund’s Adjuvant induced arthritis:

Principle:

It is a T cell and neutrophil dependent and complement independent helper (Th) 1 and (Th) 17 inflammatory cytokine associated CFA induced arthritis. Increased level of TNF-α, interferon –γ, IL-1, IL-6, IL-17 have been detected in this model. This is sensitive model to anti-inflammatory and immune inhibiting medicine and best model for pharmaclolgical and pathophysiological inflammatory process ^[48].

Procedure:

On day of zero 0.1ml of Freund’s adjuvant is injected into left hind paw of the animal. This Freund’s adjuvant consist of 6mg of Mycobacterium butyric suspended in the heavy paraffin oil. Drug treatment should start from the 14^th day i.e. from the day of adjuvant injection continued till 28^th day. The paw edema and joint thickness is measured on 7^th day, 14^th day, 21^st day and 28^th day by using a digital Vernier callipers or plethysmometer. The % inhibition of paw edema and joint thickness are calculated by using following formula:

Inhibition in paw edema/

joint thickness= 100X(1-VT/VC)

Here

VC= mean paw edema volume/joint thickness in the control group

VT=mean paw edema volume/joint thickness in the test group.

In radiological analysis radiographic are taken by the using X-ray apparatus for the joint of hind paw for evaluate the bone damage. Histopathological studies of ankle joint have been noticed by staining with eosin and hematoxyline. ^[49].

Carrageenan Induced Paw Edema in Rats:

It produce acute to chronic inflammatory responses. The acute response appears to be similar to rheumatoid arthritis. Hydrolysed carrageenan induces inflammation by inhibiting the DNA synthesis also effects on chromium release and cause cell death. ^[50].

Procedure:

Arthritis can be induced by the injection of 1% carrageenan. The paw volume of the animal can be measured within 6 hours by plethysmometer. Acute inflammation is induced to the animal by sub planter injection of freshly prepared 1% carrageenan in normal saline. Increasing paw volume is determined at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6 hours ^[51].

Using the following formula the paw volume is measured

% inhibition of paw volume= 100X(1-VT/VC)

Here

VT= mean paw volume in control group

VC=mean paw volume in drug treated group.

Transgenic mouse model of RA:

This genetic model can give valuable details about the role of genes in inflammatory process. In RA two well known models are available one is K/BxN mouse model and Human TNF- transgenic model.

K/BxN mice model:

In this animal model arthritis can be develop spontaneously. This animal model are generated by crossing KRN-C57BL/6 T cell receptor transgenic mice with NOD mice. Arthritis is caused by the immune response to the enzyme glucose 6-phosphate isomerase. Symptoms of can be observed at 4-4 weeks of age animal ^[52]

Human TNF-transgenic mice:

Human TNF-transgenic mice (Tg197) mice will express high level of soluble human TNF-α and it will undergo spontaneous development of arthritis. Mice are generated by crossing human TNF transgenic mice with RAG-1 knockout mice, which have no T cell and B cells. This is very effective model for study the anti-TNF therapies and it also used for testing the other biologics and small molecules^[53].

Diabetes Mellitus via Arthritis Mechanism:

Diabetes mellitus is a disorder that shows the increasing the blood glucose level. Inflammation may cause insulin resistance and DM through many mechanism. The major inflammatory mediators such as TNF-α and IL-6 will block the function of insulin at the receptor level ^[54-57].Some In vitro studies have been reported that TNF-α will inhibit the tyrosine phosphorylation and subsequent activation in the insulin receptor as well as insulin receptor substrate 1 ^[58]. In other hand IL-6 plays a major role in the insulin resistance in DM. IL-6 will degrade the insulin molecule. The increasing level of IL-6 have been observed in women who later development of type 2 DM.

Table:2 Role of mediators in the pathophysiology of Diabetes mellitus

Name of the Mediators

Biological action

TNF-α

Inhibit the insulin receptor tyrosine kinase pathway

IL-6

Damage insulin receptor or destroy the insulin molecule.

Commonalities between the pathophysiology of insulin resistance (IR) and rheumatoid arthritis (RA). A chronic inﬂammatory condition is maintained in patients with RA by the activation and persistence of proinﬂammatory cytokines Adipose tissue is an important source of proinﬂammatory cytokines. Activation of these cytokines leads to IR and other extraarticular manifestations of RA. IL-1 interleukin 1; TNF-α

REFERENCE:

1. The free dictionary.Com >arthritis in turning citing:

The American Heritage Science Dictionary Copy right 2005

2. Arthritis. Collins Dictionary.com. Collins English Dictionary-Complete & Unabridged 11^th edition. Retrieved Novermber 21, 2012.

3. Patil M, KandhareA, Bhise S. Anti-arthritic and anti-inflammatory activity of Xanthium strumariumL. ethanolic extract in Freund’s complete adjuvant induced arthritis. Biomedicine & Aging Pathology. 2012; 2(1)6-15.

4. Paval J, Kitheri SK, Potu BK, Govindan S, Kumar R, Narayanan S, et al. Anti-arthritic potential of the plantJusticiagendarussaBurnmF. Clinics.2009; 64(4):357-62.

5. BanjiD, Banji O, Reddy K, Pinnapureddy J, Kumar A. Evaluation of the concomitant use of methotrexate and curcumin on Freund’s complete adjuvant-induced arthritis and haematological indices in rats. Indian Journal of Pharmacology 2011; 43(5):546-50.

6. Murugananthan G, Kumar SG, Sathya CP, Mohan S. Anti-arthritic and anti-inflammatory constituents from medicinal plants. J App Pharm Sc.2013; 3:161-4.

7. Masi S, Sinnathambi A, Kapase C, Bodhankar S, Mahadik K. Anti-arthritic activity of standardised extract of Phyllanthusamarus in Freund’s complete adjuvant induced arthritis.Biomedicne& Aging Pathology. 2011; 1(3):185-90.

8. Ahlmen M, Svensson B, Alertsson K, Forslind K, Hatstrom I. Influence of gender on assessments of disease activity and function in early rheumatoid arthritis in relation to radiographic joint damage. Annals of the Rheumatic Diseases.2009; 69(1):230-33.

9. Patel P, Patel D, Patel N. Experimental investigation of anti-rheumatoid activity of Pleurotussajorcajuin adjuvant-induced arthritic in rats. Chin J Nat Med2012; 10:0269-74

10. Shin H, Jeong H, Na H, Hong S, lee S, Lee K et al. daeganghwal-tang inhibits the stem cell factor-induced migration and inflammatory cytokines secretion in mast cells. Journal of .Ethanopharmacology.2003; 85(1):157-161.

11. Kore KJ, Shete RV, Anti-Arthritic activity of hydro alcoholic extract of Lawsoniainnermisagainst adjuvant arthritis. Int.J. Drug dev & research. 2011; 3(4):217-224.

12. Kumar V, Cortan RS, Basic pathology, 7^th edition, New Delhi, Elsevier. 2005; 163-139.

13. Gabriel S, Crowson C, Kremers H, Doran M, Turesson C, O’Fallon W et al. Survival in rheumatoid arthritis: a potential-based analysis of trends over 40 years. Arthritis & Rheumatism. 2003; 48(1):54-58.

14. Smolen J, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nature Reviews Drug Discovery. 2003; 2(6):473-488.

15. Smolen J, Aletaha D, Koeller M, Weisman M, Emery P. New therapies for treatment of rheumatoid arthritis.TheLancent. 2007; 370(9602):1861-74.

16. WeyandC.The influence of HLA-Drb1 genes on diseases severity in rheumatoid arthritis. Annals of Internal Medicine.1992; 117(10):801-06.

17. Plenge R. Rheumatoid arthritis genetics:2009 update. CurrRheumatol Rep. 2009; 11(5):351-56.

18. Klareskog L, Padyukov L, Alfredsson L. Smoking as a trigger for inflammatory rheumatic diseases. Current Opinion in Rheumatology. 2007; 19(1):49-54.

19. Getts M, Miller S. 99^thDahlem conference on infection, inflammation and chronic inflammatory disorders:triggering of autoimmune diseases by infections.Clinical& Experimental Immunology.2010; 160(1):15-21.

20. Smolen J, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nature Reviews Drug Discovery. 2003; 2(6):473-488.

21. Samanta R, Shoukrey K, Griffiths R. Rheumatoid arthritis and anaesthesia. Anaesthesia. 2011; 66(12):1146-1159.

22. Epstein F, Choy E, Panayi G. Cytokine Pathways and Joint Inflammation in Rheumatoid Arthritis. New England Journal of Medicine. 2001; 344(12):907-916.

23. Lee D, Kiener H, Agarwal S, Noss E, Watts G, Chisaka O et al. Cadherin-11 in Synovial Lining Formation and Pathology in Arthritis. Science. 2007; 315(5814):1006-1010.

24. Kyung Chang S, Gu Z, Brenner M. Fibroblast-like synoviocytes in inflammatory arthritis pathology: the emerging role of cadherin-11. Immunological Reviews. 2010; 233(1):256-266.

25. Hochberg M, Johnston S, John A. The incidence and prevalence of extra-articular and systemic manifestations in a cohort of newly-diagnosed patients with rheumatoid arthritis between 1999 and 2006. Current Medical Research and Opinion. 2008; 24(2):469-480.

26. Hochberg M, Johnston S, John A. The incidence and prevalence of extra-articular and systemic manifestations in a cohort of newly-diagnosed patients with rheumatoid arthritis between 1999 and 2006. Current Medical Research and Opinion. 2008; 24(2):469-480.

27. Dayer J, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology. 2009; 49(1):15-24.

28. Pollard L, Choy EH, Scott DL. The Consequences of rheumatoid arthritis :quality of the life measures in the individual patient. ClinExpRheumatol 2005; 23:43-52.

29. McInnes I, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007; 7(6):429-442.

30. Panichi V, Miliori M, De pietro S et al. The link of biocompatibility to cytokine production.Kidney Int. 2000; 58:96-103.

31. Sattar N. Explaining How "High-Grade" Systemic Inflammation Accelerates Vascular Risk in Rheumatoid Arthritis. Circulation. 2003; 108(24):2957-2963.

32. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. New England Journal of Medicine.1995; 332(20):1351-1362.

33. Schett G. Cells of the synovium in rheumatoid arthritis. Arthritis Res Ther2007; 9:203.

34. Kudo O, Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou N. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone. 2003; 32(1):1-7

35. Lally F, Smith E, Filer A, Stone M, Shaw J, Nash G et al. A novel mechanism of neutrophil recruitment in a coculture model of the rheumatoid synovium. Arthritis Rheum. 2005; 52(11):3460-469.

36. De Benedetti F, Rucci N, Del FattoreAet al. Impaired skeletal development in interleukin-6 transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum 2006; 54(11):3551-563.

37. Poli V, Balena R, Fattori E et al. Interleukin-6 deficient mice are protected from one loss caused by estrogen depletion. EMBO J. 1994; 13:1189-1196.

38. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen B et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. Journal of Clinical Investigation. 2004; 113(9):1271-1276.

39. Nalbandian A, CrispÃn J, Tsokos G. Interleukin-17 and systemic lupus erythematosus: current concepts. Clinical & Experimental Immunology. 2009; 157(2):209-215.

40. Brandt K. The Role of Analgesics in the Management of Osteoarthritis Pain. American Journal of Therapeutics. 2000; 7(2):75-90.

41. Burian M, Geisslinger G. COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites. Pharmacology & Therapeutics. 2005; 107(2):139-154..

42. V Jaya Sankar Reddy et al. JGTPS, 2014, Vol.5(4):2061-2073.

43. Donahue K. Systematic Review: Comparative Effectiveness and Harms of Disease-Modifying Medications for Rheumatoid Arthritis. Annals of Internal Medicine. 2008; 148(2):124.

44. Richard A. Harvey. Lippincott’s illustrated reviews, Pharmacology 5^th edition. 538-543.

45. Hegen M, Keith J, Collins M, Nickerson-Nutter C. Utility of animal models for identification of potential therapeutics for rheumatoid arthritis. Annals of the Rheumatic Diseases. 2007; 67(11):1505-1515.

46. Bevaart L, Vervoordeldonk M, Tak P. Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?. Arthritis & Rheumatism. 2010; 62(8):2192-2205.

47. Lee J, Kim S, Kim T, Lee S, Yang H, Lee D et al. Anti-inflammatory Effect of Bee Venom on Type II Collagen-Induced Arthritis. The American Journal of Chinese Medicine. 2004; 32(03):361-367.

48. Bevaart L, Vervoordeldonk M, Tak P. Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?. Arthritis & Rheumatism. 2010; 62(8):2192-2205.

49. Mythilypriya R, Shanthi P, Sachdanandam P. Therapeutic effect of Kalpaamruthaa, a herbal preparation on adjuvant induced arthritis in wistar rats. Inflammopharmacology. 2008; 16(1):21-35.

50. Pandey S. Arthritis an autoimmune disorder: Demonstration of In vivo anti-arthritic activity. Inter J Pharm Life Sci. 2010; 1(1):38-43.

51. Buadonpri W, Synthetic Curcumin inhibits carrageenan induced Paw Edema in rats. J Health Res. 2009; 23(1):11-16.

52. Keffer J, probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, et al. Transgenic mice expressing human tumor necrosis factor: a predictive genetic model of arthritis. EMBO J.1991; 10:4025-4031.

53. Li P, Schwarz E. The TNF-? Transgenic mouse model of inflammatory arthritis. Springer Seminars in Immunopathology. 2003; 25(1):19-33.

54. Festa A, D'Agostino R, Tracy R, Haffner S. Elevated Levels of Acute-Phase Proteins and Plasminogen Activator Inhibitor-1 Predict the Development of Type 2 Diabetes: The Insulin Resistance Atherosclerosis Study. Diabetes. 2002; 51(4):1131-1137.

55. Liu S. A Prospective Study of Inflammatory Cytokines and Diabetes Mellitus in a Multiethnic Cohort of Postmenopausal Women. Arch Intern Med. 2007; 167(15):1676.

56. Meigs J, O'Donnell C, Tofler G, Benjamin E, Fox C, Lipinska I et al. Hemostatic Markers of Endothelial Dysfunction and Risk of Incident Type 2 Diabetes: The Framingham Offspring Study. Diabetes. 2006; 55(2):530-537.

57. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin -6 and risk of the developing type 2 diabetes mellitus. JAMA 2001; 286(3):327-334.

58. Hotamisligil G, Murray D, Choy L, Spiegelman B. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proceedings of the National Academy of Sciences. 1994; 91(11):4854-4858.

Received on 02.08.2018 Modified on 11.09.2018

Research J. Pharm. and Tech 2018; 11(11): 5212-5218.

DOI: 10.5958/0974-360X.2018.00951.4

Cytokine	Role in the disease process
TNF-α	Local Effect	Increased monocyte activation, cytokine release, PG release^[29] T-cell apoptosis, clonal regulation^[29] Decreased synovial fibroblast, proliferation^[29]
	Systemic Effect	Acute-phase protein production^[30]
	Cardiovascular disease promotion^[31]	Fatigue and depression^[32]
IL-6	Local Effect	Osteoclast activation^[33-34] Neutrophil recruitment^[35]
IL-6	Systemic Effect	Osteoporosis^[36-37] Anaemia( via hepcidin production)_[
IL-1	Local Effect	Osteoclast activation^[29] Endothelial cell adhesion molecule expression^[29]
IL-1	Systemic Effect	Acute phase protein production^[30] Cardio vascular disease promotion^[31]
IL-17	Facilitation of T-cell infiltration and activation^[39] Amplification of immune response(by induction of IL-6 production^[39]