INTRODUCTION:

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that primarily affects multiple joints, occurring in 0.5–1.0% of the world’s population. Rheumatoid arthritis (RA) is more common in women than in men¹. The peak incidence in females coincides with menopause when the ovarian production of sex hormones drops markedly. While in men it occurs at 60–70 years of age coinciding with the fall of biologically active testosterone. Macrophages, T cells and B cells infiltrate the synovium that lines the joints, while the synovial fluid is dominated by neutrophils. Chronic inflammation leads to destruction of joint cartilage and bone. Several findings indicate the involvement of sex hormones in RA³. For example, the female to male incidence ratio is 4–5:1 before 50 years of age, and 2:1 for patients with a later onset, and the peak incidence in women coincides with menopause. It has been shown that estrogens can affect the disease course of RA in humans, and in animal models. B cells are not merely antibody-producing cells, but they might also participate in the disease process by producing cytokines and effectively presenting antigen to specific T cells⁴.

Pathophysiology of rheumatoid arthritis:

Variations in immune balance oddly results in high cell death or increased cellular proliferation leading to a pathological disease such as RA. Among various proinflammatory cytokines, TNF-α and IL-6 have been proven to play critical roles in the development of RA. Proved as biological agents that antagonize TNF-α and IL-6 are highly effective in treatments for RA⁵.

It is thought that the synovial hyperplasia is mediated, by inflammatory cells these are T-cells, B-cells, macrophage, neutrophils and macrophage like synoviocytes, which upon activation produce proinflammatory cytokines such as IL-1, TNF-α and IL-6 as represented in Figure 1. These cytokines are speculated to stimulate the overgrowth of Fibroblast like Synoviocytes (FLS) to form a synovial tissue mass called a pannus, which invades bone and cartilage via the production of matrix degrading enzymes from (FLS) and articular chondrocytes⁶.

Figure 1. Immunopathogenesis

Role of T cells

In RA, T cells represent a large proportion of the inflammatory cells invading the synovial tissue, causing T cell activation and migration into the synovium occurs as an early consequence of the disease. These cells adopt a pro-inflammatory phenotype and can activate for example B cells and synovial macrophages via cytokine production. In one of the study using B10q mice, which are highly susceptible to CIA, lack of CD4+ T cells resulted in decreased susceptibility to disease and lower levels of CII antibodies, whereas lack of CD8+. T cells did not significantly affect the disease⁷. It has been demonstrated that Mice and humans lacking the key transcription factor for Treg, forkhead box protein 3 (Foxp3), develop multi-organ autoimmune disease⁸. The balance of CD4+ Th1 and Th2 cells has been suggested to play a role in the pathogenesis of RA. The Th1 category is generally categorized specifically for production of IFN-α and IL-2, and by the stimulation of cell-mediated immunity, whereas the Th2 subset category specifically produces IL-4 and stimulates humoral immunity. Based on analysis of IFN-α and IL-4 production, a dominance of Th1 cell activity over Th2 cell activity has been shown in the inflamed joints of RA patients⁹.

A large proportion of the T cells infiltrating the joints in RA produce the pro-inflammatory cytokine IL-17. IL-17 promotes the production of pro-inflammatory mediators from cells present in the joint including synovial fibroblasts, monocytes, macrophages and chondrocytes, which result in cartilage damage and bone erosion¹⁰.

Role of B cells

B lymphocytes are important in the pathogenesis of RA, by production of antibodies to Collagen Type-II (CII), and for T cell activation. Anti-Collagen Type-II antibodies generally bind to the articular cartilage and initiate complement activation, which recruits inflammatory cells to the site. Series of recruitment is as follows neutrophils then monocytes and lymphocytes¹¹.

Antibodies to CII have been detected in serum and synovial fluid of patients with RA, and CII antibody producing B cells have been found in synovial fluid and synovial tissue. Transfer of CII-antibodies can induce arthritis in mice. Administration of B cell-depleting anti-CD20 antibodies has been shown to be a successful treatment for some RA patients.¹²

Hormone Therapy:

Estrogens influence the immune system in a versatile way; nevertheless many more need to completely understand the influence of estrogen. Estrogen posses stimulatory and inhibitory effects on different parts of the immune system, and some functions may not be the same in vivo as in vitro. Clinical trials of postmenopausal RA patients have shown that HRT decreases disease activity, improved probability of a joint protective effect has been found. The bone and cartilage turnover is reduced by HRT. Thus, the treatments through estrogen also have several important effects in postmenopausal RA. However, HRT is no longer recommended for long-term therapy due to the risk of serious side effects.¹³

Various researches conducted at different phases by hormone for arthritis therapy:

Rachon et al demonstrated that the production of several cytokines is influenced by menopause. Thus, the serum levels of IL-1, IL-6, TNF and M-CSF have been shown to increase after natural or surgical menopause, and decrease upon estrogen therapy.¹⁴ Eghbali et al demonstrated that in early menopausal women it has been demonstrated that the expression of RANKL is up-regulated on T cells, B cells and pre-osteoblastic bone marrow cells.¹⁵

Kazuki Inoue et al demonstrated that estrogen and progesterone treatment might be effective for therapeutic approaches to RA. Hormone treatment may cause various adverse effects, including increased risks of endometrial and breast cancer, venous thromboembolism and gallbladder disease. Therefore, selective estrogen receptor modulators (SERMs) and selective progesterone receptor modulators (SPRMs) have been developed to reap the benefits of the hormones while preventing their side effects. Indeed, it was reported that tamoxifen, one of the SERMs, exerted beneficial effects on SLE in NZB/NZW F1 female mice.¹⁶Forsblad et al In a randomized controlled prospective 2-year trial of 88 postmenopausal women with RA, it was shown that HRT improved both clinical and laboratory signs of disease activity.¹⁷

Holmdahl et al. demonstrated that that estradiol treatment of CIA in mice suppresses disease progression.¹⁸

Straub et al demonstrated that 2-methoxyestradiol is an endogenous estradiol metabolite that Shows inhibitory effects on cell proliferation and neoangiogenesis.¹⁹ Riggs et al demonstrated Estrogen also influences the skeleton through the endocrine system, increasing the production of insulin-like growth factor 1 (IGF-1), which has anabolic effects on bone.²⁰ Ernst et al demonstrated that estrogen has been shown to increase the expression of OPG, BMP-6, TGF and IGF-1, which results in osteoblast formation and increased osteoclast apoptosis.²¹

CONCLUSION:

It is remarkably concluded that B cells, T cells, proinflammatory cytokines, neutrophils, macrophages play a important role in the pathogenesis of arthritis. Collectively it has been demonstrated that deficient of sex hormones also as an important cause of rheumatoid arthritis in females at early stage. Many clinical trials, research activities and In vivo studies demonstrated the relevant role of hormone replacement therapy in improving therapeutic conditions of females suffering from arthritis.

ACKNOWLEDGEMENT:

The authors are thankful to Director, University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur (C.G.) India for this study and UGC-MRP-41-748-2012, UGC-RA 70-371/2012for financial assistance relating to this work.

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Received on 03.10.2015 Modified on 15.10.2015

Research J. Pharm. and Tech. 9(2): Feb., 2016; Page 170-172

DOI: 10.5958/0974-360X.2016.00030.5