The Autoimmune Disease Of Rheumatoid Arthritis Biology Essay

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Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints. It is associated with increased mortality rates as compared to the healthy population. The actual cause of rheumatoid arthritis is unknown although several factors accelerating its progression are outlined. This review enlists various histopathological changes and encompasses a note on its applicability in target specific delivery with the aid of antibodies. There are various first-line, second-line and newer biological treatments available. This review gives brief detail of the novel approaches for the delivery of the targeted as well as non targeted systems like oral, topical, nasal and parenteral and the recent advancements that have been achieved. Moreover it also gives an account of the amendment that can be made for future with the use of biotechnology, the application of gene profiling and gene array techniques.

Keywords: Antibodies, cytokines, inflammation, line of therapy, rheumatoid arthritis, targeted drug delivery system


Rheumatoid arthritis is an autoimmune disorder that causes chronic inflammation of the joints, tissues around the joints, as well as other organs of the body causing cartilage and bone destruction resulting into the gradual immobility of the joints. Rheumatoid arthritis has been perceived long back since the 17th century in the American and European populations. As per American journal of medicine more than 1% population in the world suffers from rheumatism, where women are at a higher risk than men [1]. According to World Health Organization the prevalence of rheumatoid arthritis in most industrialized countries varies between 0.3 to 1%, whereas in developing countries it is much lower [2]. The European league against rheumatism aspires to reduce the burden of disease, prevention, rehabilitation of disease and improve the treatment [3]. In RA autoimmune antibodies are produced in patient's blood along with the inflammatory responses and development of pannus in the synovium often leading to the destruction of articular cartilages and inflammation of the joints. The American College of Rheumatology focuses on twofold treatment, first to alleviate the current symptoms and secondly to prevent the future destruction of joints [4]. In practical world, though pain relievers and steroids are used in majority of cases, they have been replaced by more popular biological agents. Controlled and targeted therapy increases effectiveness of drug, reduces dosing interval and minimizes the dose required for the therapeutic action. Looking to the future prospects, combination therapy is showing better potential than prescribing individual drugs to rheumatic patients [5].

Impact of arthritis

2.1 The mortality and co-morbidities

As compared to general population, RA is associated with the surplus mortality rate of about 25% [6]. Most of the deaths in RA are caused due to co-morbidity and the presence of coexistent disease, which accounts for CVS (42%), infections (9%), renal disease (8%), pulmonary disease (7%) and GI diseases (4%) [7]. CVS diseases are most prominent to cause death which includes systemic inflammation and other risk factors like dyslipidemias and homocystenemia due to treatment with sulphasalazine or methotrexate [8]. The overall predictors for mortality in RA are patient's age, sex, disease duration, functional status, co-morbidity and extra-articular manifestation like vasculitis [9].

2.2 The economic impact of RA

Arthritis, the common cause of disability, is a hefty growing public health problem in the United States resulting in cost of 128 billion dollars annually [10]. The WHO assesses the economic burden of RA on three levels- direct, indirect and psychosocial costs [2]. The major driver for direct cost (medical) is inpatient care. However, the available very effective but expensive treatment such as tumor necrosis factor blocking agents increases the cost of therapy. The indirect costs (loss of earnings) are mostly due to the number of days absent from work. As a result, the indirect costs in working age patients due to work disability may be significantly higher than the direct costs [11, 12].

Histopathological changes in rheumatoid arthritis

The ground for the rheumatic arthritis is unknown although certain theories have been postulated describing its probable mechanism like infections of viruses, bacteria or fungi, environmental factors, smoking of tobacco and some person also do believe it to be genetically inherited. Presuming the above factors to be the root cause of the disease the general mechanism can be drawn by considering them as antigens which are presented to the T cells by professional antigen-presenting cells (APC) such as dendritic cells, macrophages, or activated B cells, which follows binding of antigenic peptides to class II MHC molecules [13].

Also theories have been formulated linking the initiation of Rheumatic arthritis with the inflammation in synovial lining, synovial tissues, release of inflammatory mediators and also bone erosions. The inflammation of synovial lining is important mascot which is characterized by pronounced angiogenesis; cellular hyperplasia; an influx of inflammatory leucocytes including T cells, B cells, macrophages, plasma cells and changes in the expression of cell-surface adhesion molecules, proteinases, proteinase inhibitors, and many cytokines [14]. Synovial fibroblast lining differs from deeper synovial fibroblast lining both morphologically as well as biologically and these differences can be attributed to the changes in transcriptional genes and intracellular signaling cascade [15]. Initially the tissue edema and fibrin deposition takes place, responsible for the joint swelling and pain followed by synovial lining becoming hyperplastic; commonly ten or more cells deep with macrophage like and fibroblast like synoviocytes. Along with this the sublining also undergoes alterations cellular number and content, with prominent infiltration of mononuclear cells including T cells, B cells, macrophages, and plasma cells which again organize into discrete lymphoid aggregates with germinal centers. Hyperplasia of the intimal lining results from a marked increase in macrophage-like and fibroblast-like synoviocytes. Synovial-vessel endothelial cells transform into high endothelial venules early in the course of the disease which facilitate the transport of leucocytes from blood stream to synovial tissue [16].

The other characteristic feature of RA is Pannus- a locally invasive synovial tissue, which is distinct from other regions of synovium and shows phases of progression. Initially Pannus penetrates cartilage mainly composing of mononuclear cells and fibroblasts, [17] with high level expression of metalloproteinases by synovial lining cells whereas in the later stages cellular pannus is replaced by fibrous pannus comprising of a minimally vascularised layer of pannus cells and collagen overlying cartilage [18].

The macrophage like synoviocytes led to overproduction of cytokines mainly IL-1 & TNF-α [19] and IL-6, IL-8, IL-15 and, recently reported, activation-induced, T-cell derived(such as IL-2 and 17, and interferon gamma), chemokine-related cytokine/lymphotactin, [20] macrophage migration inhibitory factor, [21] fibroblast growth factor and platelet derived growth factor in smaller quantities. These endogenous components stimulate synovial tissue effector functions, including proliferation, metalloproteinase expression, adhesion-molecular expression, secretion of other cytokines, and prostaglandin production-all of which may have a role in RA pathogenesis [19].

The fibroblasts like synioviocytes have been shown to invade cartilage when implanted along with cartilage a behavior correlating with joint destruction. Locally expressed degradative enzymes, including metalloproteinases, serine proteases and aggrecanases, digest the extracellular matrix and destroy the articular structures. Aberrant adhesion molecule expression leads to uncontrolled binding of T cells to synovial type B cells, resulting in excess release of matrix metalloproteinases. Matrix metalloproteinases cause cartilage and bone degradation by means of extracellular matrix remodeling and degradation [19]. Erosions in RA also relates to osteoclast-mediated bone resorption that is regulated by RANKL expressed by T cells and synoviocytes who also in the presence of cytokines like TNF-a and M-CSF, contribute to osteoclast maturation and activation. The mitogen-activated protein (MAP) kinases and transcription factor activator protein-1 (AP-1) regulate the production of cytokines and matrix metalloproteinases [22].

Rheumatoid factor, a group of autoantibodies (IgM, IgG, and IgA) is the classic autoantibody in rheumatoid arthritis that recognizes the Fc portion of IgG [23]. The complete role of RF in RA pathogenesis is unclear although autoimmune response to RA may be due to the development of RF complexes which fix complement, recruit macrophages, neutrophils, and lymphocytes, and release cytokines upon ligation of Fc-gamma receptors on macrophages that together lead to inflammation [24, 25]. IgA RF may lead to excessive intra-articular tissue growth factor-b secretion, creating the bone erosions seen in RA [26].

Angiogenesis is highly active in rheumatoid arthritis providing oxygen and nutrients to the hypertrophic synovium, and also provides the means for recruitment of inflammatory cells to the joint anatomical compartment [27, 28].

Almost all of the inflammatory mediators linked to arthritis have been regulated by the transcription factor nuclear factor-kB [29] whose activation has important role in progression of disease and inflammation [30-33]. The inducers and various targets of NF-kB for the treatment of RA are described in Table 1 [34].

Table 1, Inducers and various targets of NF-kB for the treatment of RA.


Inducer of NF- kB




IL1, TNF -α

Inflammation, Expression of metalloproteinase and adhesion molecules, Prostaglandin production, Angiogenesis and secretion of other cytokines

IL-1, IL-2, IL-6, IL-8, IL-15, IL-17, IL-18, TNF α

T Cell

CD40L, FasL

Recruitment of inflammatory cells

IL-8, MCP-1, ICAM-1, VCAM -1, GM -CSF


B Cell

CD20, CD40L, CD+4T cell

T Cell activation, Leucocyte infiltration and angiogenesis

IL-1, IL-4, IL-6, IL-10, TNF- α

Nerve growth factor

BDNF, NT-3, NT- 4, NT-5

Expression of IL 2 receptor on T and B cell, Activation of T cell, B cell Basophiles, PI 3 kinase, RAS and PLC, Migration of leucocytes, Mast cell degradation and NOS induction

MMP -1, TNF-α, IL-1, IL-2, IL-6, IL-8 ,IL-12, adhesion molecule, collagenase -1

Growth factor



TGF (TGF b1)

Activation of inflammatory cell and Promote chemotaxis




COX -2,


FGF (FGF acidic and FGF basic)

Inhibit type ІІ collagen and proteoglycan synthesis, Induction of MMPs, Production of prostaglandin and NO and Chemo-attractant for endothelial cells


Act as a mitogen, Chemo-attractant for smooth muscle cell and macrophages, Induce expression of IL 1β, IL 8 and MMPs


IL-1β, IL-8,


Viral protein

HTLV-1 tax

Production of MMPs, Remodeling and destruction of extracellular matrix

MMP-1, MMP-3, MMP-9, MMP-13

Bacterial products


Oxidative stress

Superoxide, peroxide

Proliferation of cells

C Myc, cyclin D

Ischemia/ reperfusion


Radiation, chemotherapy

Anti apoptosis and activation of anti apoptotic genes


c IAP-1, c IAP-2

Line of therapy for arthritis

At present time, the absolute cure for rheumatoid arthritis is unavailable. The main objective for treating arthritis is to diminish joint inflammation, pain, avoid joint deformation and to improve joint function. The first line agents used for treatment like NSAIDs, selective COX-2 inhibitors and steroids are intended to suppress the pain manifested in arthritis and are not said to prevent destruction of joints. This joint deformation can be prevented by second line agents like DMARDs and biological drugs [35, 36].

First-line medications

Nonsteroidal anti-inflammatory drugs

NSAIDs are categorized into salicylates (with aspirin as prominent member), arylalkanoic acids (Diclofenac, indomethacin, nabumetone, sulindac), 2-arylproprionic acids or profens (ibuprofen, flurbiprofen, ketoprofen, naproxen), N-arylanthranilic acids or fenamic acids (mefenamic acid, meclofenamic acid), pyrazolidine derivates (phenylbutazone), oxicams (Piroxicam, meloxicam) and sulfonanilides (nimesulide). These NSAIDs exert their action by inhibiting the enzyme cyclo-oxygenase (COX), which catalyzes the conversion of arachidonic acid to prostaglandins and thromboxane. Two forms of COX have been identified-COX-1, which is constitutively expressed in most tissues and organs, and the Inducible enzyme, COX-2, which is localized primarily to inflammatory cells and tissues. The analgesic, antipyretic and anti-inflammatory effect shown by aspirin at risk of GI bleeding is due to inhibition of prostaglandin production by blocking the COX enzyme, whereas the nonaspirin NSAIDs exert their action by inhibiting PG G2/H2 synthase, blocking both COX-1 and COX-2 isozymes, [37] thereby inhibiting access of arachidonic acid to the catalytic site and thus ultimately inhibiting the synthesis of prostaglandin, PGI2, and thromboxanes. NSAIDs being structurally diverse differ in pharmacokinetic and pharmacodynamic properties, ultimately sharing the same mode of action and decreases tissue inflammation, pain, and swelling. The most familiar side effects of aspirin and other NSAIDs include ulcers, abdominal pain, stomach upset, and gastrointestinal bleeding [43]. Drugs which act on both COX-1 and COX-2 inhibitors appeared more effective anti-inflammatory agents than selective COX-2 inhibitors [38].

COX-2 inhibitor

COX-2 inhibitors like Celecoxib (Celebrex), Rofecoxib (Vioxx) and Valdecoxib (Bextra) shows their action of reducing inflammation and relieving the pain by inhibiting the enzyme cyclooxygenase-2 found in the inflamed area preventing the production of three main groups of prostanoids namely the prostaglandins, prostacyclins, and thromboxanes [39]. In an animal model, carragenan was injected into footpad to produce edema with accumulation of COX-2, m-RNA and thromboxanes. A selective COX-2 inhibitor inhibited this edema, but had no effect on PG production. These data suggested regarding the selective inhibition of COX-2 and its superiority over existing NSAIDs [40].


Over the past several decades, Glucocorticoids have been the choice of treatment for controlling the sign and symptoms of RA. The selection of corticosteroids either as first line or second line agent differs in the perspectives of scientists. Possible mechanisms of action of glucocorticoids in RA include inhibition of macrophage function, antigen presentation and class II molecule expression, and reduction in adhesion molecule expression [41]. Corticosteroids like Betamethasone (Celestone), Budesonide (Entocort), Cortisone (Cortone), Dexamethasone (Decadron), Hydrocortisone (Cortef), Methylprednisolone (Medrol), Prednisolone (Prelone), Prednisone (Deltasone) and Triamcinolone (Kenacort) can be administered either orally or intra-articularly into tissues and joints reducing the inflammation and restoring the joint mobility. In addition to reducing acute inflammation, glucocorticoids have been shown to retard erosion formation in studies of early RA, although the evidence is conflicting Corticosteroids give promising result when used for shorter duration during severe flares of disease progression or when patients do not respond to NSAIDs. Corticosteroid inhibits induction of COX, thus preventing the release of collagenase and lysosomal enzymes, and reduces macrophage phagocytosis and IL-1 secretion [42]. Glucocorticoids act like immune-suppressant and demolish the cytokine gene transcription. However, they also impede the function of white blood cells which destroy the foreign bodies resulting into increased susceptibility to infection. The other side effects of corticosteroids include weight gain, facial puffiness, thinning of the skin and bone, easy bruising, cataracts, muscle wasting, and destruction of large joints, such as the hips [43].

Second line medication

Disease-modifying anti-rheumatic drugs [DMARDs]

The first line medications such as NSAIDs and corticosteroids can reduce joint inflammation and pain, but does not claim to prevent the joint destruction or deformation. To prevent progressive damage to cartilages, bones, and adjacent soft tissues, medication other than first line agents are needed. The second line medication or slow acting or disease modifying antirheumatic drugs are a group of hetero compounds that takes longer time to show their effect in reducing the joint swelling and pain, decreasing acute-phase markers, limiting the progressive joint damage, and improving the joint function [44-47]. DMARDs being partly effective and poorly tolerated in long term therapy, it requires patient to undergo frequent monitoring of blood and physical examinations for toxic effects [48]. DMARDs are immunosuppressant associated with some common side effects like, skin rash, sore mouth, kidney damage with proteinuria, bone marrow damage with anemia and leucopenia, fever, chills, metallic taste, stomach upset, and easy bruising [43].The DMARDs used along with their mechanism of action has been given in Table 2.

Table 2, Mechanism of action of DMARDs.



Mechanism of action


Chloroquine and Hydroxychloroquine (Ploquenil) (antimalarials)

Suppression of IL-1 &TNF-α induced apoptosis of inflammatory cells and increase chemotactic factors it operates by inhibiting lymphocyte proliferation, phospholipase A, antigen presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1


Sulphasalazine (Azulfidine)

It mayact by scavenging the toxic oxygen metabolites produced by neutrophilsSSZ therapy decreases the production of IgM rheumatoid factor, suppresses T cell responses, and inhibits the binding of tumor necrosis factor to its membrane receptor.


Gold salts 

Aurothiomalate (Myochrysine), Thioglucose (Solganal), Auranofin (Ridaura)

Gold salts inhibit macrophage activation

Auranofin- inhibits the induction of IL-1 and TNF-α. Aurothiomalate can inhibit lymphocyte proliferation, lysosomal enzyme release, the release of reactive oxygen species from macrophages, and IL-1 production.


Azathioprine (Imuran)

Inhibits purine synthesis


Cyclosporin A (Sundimmun)


Inhibit calcineurin and reduce clonal proliferation of T cells primarily by inhibiting IL-2 synthesis and possibly also by decreasing expression of IL-2 receptors


D-penicillamine (Depen)

Decreases the number of T-lymphocytes, decreasing IL-1 production, preventing the maturation of newly synthesized collagen.


Leflunomide (Arava)

Inhibits pyrimidine synthesis, inhibitor of dihydroorotate dehydrogenase-an enzyme required for de-novo pyrimidine synthesis which arrests the cell cycle.


Methotrexate (Rheumatrex)

MTX acts as a folate antagonist by inhibiting tetrahydrofolate reductase.


Minocycline (Dynacin, Minocin)

Inhibits 5 lipoxygenase


Mycophenolic acid

restrains proliferation of both T and B lymphocytes


Since the currently available DMARDs have different mechanisms of action and limited efficacy as monotherapeutic agents, combination strategies have been implemented in both established as well as early stage of RA [53]. Mono-therapies or binary therapies block only a fraction of the inflammatory processes that contribute to arthritis [54], while leaving other mediators of inflammation unconstrained. Therefore combination DMARD therapy is implemented for decreasing the inflammatory symptoms and retarding the joint destruction while maintaining a tolerable toxic-effect profile [55, 56]. More than 90% of the rheumatologists prefer combination therapy of DMARDs for the treatment [57]. Recent studies have shown that the combination of methotrexate with cyclosporine, infliximab or leflunomide; sulfasalazine with hydroxychloroquine or prednisolone; and combination of sulphasalazine, hydroxychloroquine and prednisolone increases the efficacy and alleviates the pain more effectively than the mono therapeutic agents [14].

Biological agents

Introduction of biological agents for the treatment of the chronic inflammatory joint disease rheumatoid arthritis has reinvigorated research into this debilitating disease. These agents have been shown to act both on the signs and symptoms of disease, as well as retard the progression of joint destruction. Initially, the treatments consisted of chimeric antibodies with human constant regions of light and heavy chain and the variable murine binding site for the target molecule whereby the research led to a reduction of immunogenicity, partially humanized and eventually fully human antibody production. Biological agents are also called as biological response modifiers. BRMs acting as antibodies against the inflammatory agents alter the response produced by them and in turn cause immediate relief from the pain. BRMs function by neutralizing a target cytokine or its receptor, blocking costimulation molecules, and inducing cytolysis, apoptosis or depletion of target cell molecules. At present BRMs are prescribed to only those patients who do not respond to methotrexate or DMARDs therapy. In comparison to DMARDs, the biological agents have quicker onset of action, improve patient mobility and retard the radiographic progression of joint erosions. These agents show their maximum efficacy when the treatment is initiated immediately after the onset of disease. [58-62]. Although IL-1 and TNF-α stimulate each other's production and thus, appear to be an attractive combination treatment, but at present this BRM combination therapy (e.g. etanercept and anakinra) is not a recommended treatment for RA because of the higher risk of immune supression [63]. However, BRMs in combination with methotrexate or leflunomide (DMARDs) are very effective in suppressing the clinical manifestations and retarding the progression of joint erosions [58-62]. Though BRMs appear to be an exciting therapy for arthritis it deals with several side effects like redness, irritation, increased risk of infection, increased risk of lymphoma, limited response rate and high cost [64]. The examples of biological agents with their mechanism of action are described in Table 3 [65].

Table 3. Examples of biological agents with their mechanism





TNF-α Inhibitors

Etanercept(Enbrell) Infliximab(Remicade) Adalimumab(Humira) Golimumab(CNTO 148, Simponi) Certolizumab(Cimzia)

Bind to TNF-α preventing if from bonding to TNF-α receptor thus Neutralize TNF-α

Approved for marketing

TNF-α kinoid

TNF-α antagonist

Phase II trial

IL-1 Antibody


IL-1 receptor antagonist

Approved (Kineret)


IL-1 β receptor antagonist

Phase II trial

IL-2 Antibody


Chimeric human mAb to IL-2 receptor on T cell antagonist

Approved (Simulect)


Humanized mAb to IL-2 receptor antagonist

Approved (Zenapex)

IL-6 Antibody

Toclizumab or Atlizumab

Humanized mAb against IL-6 receptor

Approved (Actemra)


Anti IL-6 antibody

Phase II trial

IL-12/ IL-23 Antibody

Ustekinumab (CNTO-1275)

mAb against IL-12 and IL-23

Phase III trail

Apilimod masylate

IL-12 and IL-23 inhibitor

Phase II trial

IL-17 Antibody


Fully human recombinant IgG1 antibody blocking action of IL-17 A

Phase III trail

LY 2439821

Anti IL-17 antibody

Phase II trial

IL-15 Antibody

Humax IL-15

Fully human antibody against IL-15

Phase I / II trial


Humanized IgG 1 antibody against Il-15

Phase II trial

T-CELL Inhibitor

Alemtuzumab Keliximab Clenoximab

Antibody against antigen of T cell like CD 52, CD 4

Trail of all drugs was discontinued because serious adverse effect like lymphocytopenia and rush


Inhibit TNF-α, inhibit T cell function without depletion of T cell

Recently approved (Orencia)


A potent variant of Abatacept

Under trial

Antibody against T cell antigen


Anti- CD 3

Phase II trial


Anti- CD 4

Phase II/III trail

B CELL Inhibitor


Chimeric mAb against CD 20, destroying B cell

Approved (Rituxan)


Human mAb against CD 20, inhibiting B cell activation

Approved (Arzerra)


Humanized anti CD 20 antibody

Phase III trail



Fully humanized mAb targeting RANKL

Approved (Prolia, AMG 162)

VEGF Antibody


Humanized mAb blocking VEGF-A

Approved (Avastin)

JAK Inhibitor

SPB 00125

Inhibit JAK and MAPK

Under clinical trial

CP 690, CP 550, ACR 20,ACR 50

JAK 3 inhibitor, prevent interferon gamma signaling

Phase II trial

c- FAS/ AP-1 Inhibitor

T 5224

ARG 098

Regulator of apoptosis

Phase I trial

GM- CSF antibody

MOR- 103

Human antibody to GM-CSF

Phase I/II trial

Natural plant products

The current conventional treatment for arthritis though being expensive causes side effects which can be prevented by transforming to the novel natural products. These natural drugs have their ability to modulate the expression of pro-inflammatory signals showing potential for treatment of arthritis. Although various agents like flavanoids, terpenes, quinones, alkaloids and polyphenols have known to modulate signals, but they do have certain limitations for their usage including lack of efficacy and severe side effects. The naturally occurring compounds with their molecular targets have been mentioned in Table 4 [66-76].

Table 4. Molecular targets of natural compounds that have anti arthritic activity.




Molecular targets