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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 details 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 changes that can be made for future with the use of biotechnology like the application of gene profiling and gene array techniques.
Keyword: Antibodies, Cytokines, Inflammation, Rheumatoid Arthritis, Targeted drug delivery system, Treatment
Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints, tissue around the joints, as well as in other organs in the body and also causes cartilage and bone destruction and so it is referred to as a systemic disease or rheumatoid disease results in gradual immobility. Autoimmune diseases are illnesses that occur when the body's tissues are mistakenly attacked by their own immune system. Patients with autoimmune diseases have antibodies in their blood that target their own body tissues, where they can be associated with inflammation . While rheumatoid arthritis is a chronic illness, meaning it can last for years. However, rheumatoid arthritis is typically a progressive illness that has the potential to cause joint destruction and functional disability. It was first found in early Native American population several thousand years ago but might have appeared in Europe after 17th century . Mainly treatment of arthritis meant for symptomatic relief and rehabitalization of individual. In practical world pain relievers and steroids are used to treat arthritis in most of the cases. Now days biological agents are being more popular. Use of Controlled and targeted therapy increases effectiveness, reduces dosing intervals and minimize dosing requirements. Combination therapy is showing better approach than prescribing individual agents to rheumatic patients.
2. Impact of arthritis
2.1.1 Mortality and co-morbidities
Rheumatoid arthritis is a common rheumatic disease, affecting approximately 1.3 million people in the United States only, according to current census data. . RA is associated with excess mortality compared with the general population. This excess mortality rate has been estimated at approximately 25% . Cardiovascular disease is the most important co-morbid cause of death in patients with RA, being reported in 42% of RA patients , it is also due to treatment with methotrexate (MTX) or sulphasalazine, hypertension, renal disease and infections .
2.1.2 The economic impact of RA
The major driver for direct costs is inpatient care. However, the available very effective but costly treatments such as tumor necrosis factor (TNF) blocking agents may lead to medication being the major cost driver. The indirect costs 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 substantially higher than the direct costs. Functional disability is strongly correlated with the direct and indirect costs in RA [5-7].
3. Histopathological changes in rheumatoid arthritis
The cause of rheumatoid arthritis is unknown. Even though infectious agents such as viruses, bacteria, and fungi have long been suspected, none has been proven as the cause. It is believed that the tendency to develop rheumatoid arthritis may be genetically inherited. It is also suspected that certain infections or factors in the environment (smoking tobacco) might trigger the activation of the immune system in susceptible individuals. This leads to inflammation in the joints and sometimes in various organs of the body, such as the lungs or eyes. An inflamed synovium is central to the pathophysiology of rheumatoid arthritis. It is histologically striking, showing pronounced angiogenesis; cellular hyperplasia; an influx of inflammatory leucocytes including T cells, B cells, macrophages, and plasma cells; and changes in the expression of cell-surface adhesion molecules, proteinases, proteinase inhibitors, and many cytokines. Almost all of the inflammatory mediators linked to arthritis have been shown to be regulated by the transcription factor nuclear factor-kB (NF-kB) . In RA there is significant difference between the superficial synovial fibroblast lining and deeper synovial fibroblast lining. Synovial fibroblast differs morphologically and biologically from normal synovial tissue. These morphological and biological changes of synovial fibroblast results from specific changes in transcriptional genes and intracellular signaling cascade. The transcription factor NF-kB is activated in RA and appears to be important for progression of disease as well as in mediating inflammation [9-12]
Table 1.Various Inducers and Targets of NF- kB Serves as a Potential Target for Treatment of RA .
Inducer of NF- kB
IL1, TNF -Î±
Inflammation; Expression of metalloproteinase and adhesion molecule; Prostaglandin production; Angiogenesis; Secretion of other cytokines
IL-1, IL-2, IL-6, IL-8, IL-15, IL-17, IL-18, TNF Î±
Recruitment of inflammatory cell
IL-8, MCP-1, ICAM-1, VCAM -1, GM -CSF
CD20, CD40L, CD+4T Cell
T Cell activationÂ ; Leucocyte infiltrationÂ ; Angiogenesis
IL-1, IL-4, IL-6, IL-10, TNF- Î±
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, PLC; Migration of leucocytes; Mast cell degradation; NOS induction
MMP -1, TNF-Î±, IL-1, IL-2, IL-6, IL-8 ,IL-12, adhesion molecule, collagenase -1
TGF (TGF b1)
Activation of inflammatory cell; Promote chemotaxis
FGF (FGF acidic and FGF basic)
Inhibit type Ð†Ð† collagen and proteoglycan synthesis; Induction of MMPs; Production of prostaglandin and NO; Chemoattractant for endothelial cells
Â Act as a mitogen; Chemoattractant for smooth muscle cell and macrophages; Induce expression of IL 1Î², IL 8 and MMPs
Production of MMPs; Remodeling and destruction of extracellular matrix
MMP-1, MMP-3, MMP-9, MMP-13
C Myc, cyclin D
Anti apoptosis; Activation of anti apoptotic genes
c IAP-1, c IAP-2
4. Medication used for the Treatment of arthritis
There is no known cure for rheumatoid arthritis to date, the goal of treatment in rheumatoid arthritis is to reduce joint inflammation and pain, maximize joint function, and prevent joint destruction and deformity. First line agents mainly involve non steroidal anti-inflammatory drugs (NSAIDs), selective COX-2 inhibitors and steroids such as glucocorticoids. Second line agents mainly include disease modifying anti-rheumatic drugs such as chloroquine, gold salts, penicillamine, cyclosporine, and several biological agents like TNF-Î± and interleukin-1 inhibitors [14-15]. First line agents are used for suppression of pain manifested in arthritis; however these agents do not prevent further destruction of joints. In contrast to first line agents, second line agents do not relieve pain but are more effective in prevention of joint destruction.
4.1.1 First-line medication
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Acetylsalicylate (aspirin), Naproxen (Naprosyn), Ibuprofen (Advil, Medipren), Etodolac (Lodine), Meloxicam, Nabumetone, Sulindac, Tolementin, Choline magnesium salicylate, Diclofenac, Diflusinal, Indomethicin, Ketoprofen, Oxaprozin, and Piroxicam are examples of NSAIDs. NSAIDs are first line medications that can reduce tissue inflammation, pain, and swelling. Aspirin, in doses higher than those used in treating headaches and fever, is an effective anti-inflammatory medication for rheumatoid arthritis. The most common side effects of aspirin and other NSAIDs include stomach upset, abdominal pain, ulcers, and even gastrointestinal bleeding .
Celecoxib (Celebrex), Rofecoxib (Vioxx), Valdecoxib (Bextra). COX-2 inhibiters inhibit the action of COX-2 enzyme found in inflamed area. COX-2 inhibitor prevent production of three main groups of prostanoids - prostaglandins, prostacyclins, and thromboxanes thus reduces inflammation and relieves pain more selectively and efficiently than NSAIDs 
Betamethasone (Celestone), Budesonide (Entocort), Cortisone (Cortone), Dexamethasone (Decadron), Hydrocortisone (Cortef), Methylprednisolone (Medrol), Prednisolone (Prelone), Prednisone (Deltasone), Triamcinolone (Kenacort). Corticosteroid medications can be given orally or injected directly into tissues and joints. They are more potent than NSAIDs in reducing inflammation and in restoring joint mobility and function. Corticosteroids are useful for short periods during severe flares of disease activity or when the disease is not responding to NSAIDs. Corticosteroids acts by inhibiting induction of COX enzyme. Moreover, corticosteroids also inhibit release of collagenase and lysosomal enzyme by reducing macrophage phagocytosis and IL-1 secretion [18[. Glucocorticoids are immunosuppressant and acts by limiting clonal proliferation of the cells, through decreasing transcription of many cytokine genes . However, they also impede the function of white blood cells which destroy foreign bodies and help keep the immune system functioning properly. The interference with white blood cell function yields a side effect of increased susceptibility to infection. Other side effects associated with corticosteroids, especially when given in high doses for long periods of time 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 [1, 37].
4.1.2 Second line medication
Disease-modifying antirheumatic drugs
While first line medications (NSAIDs and corticosteroids) can relieve joint inflammation and pain, they do not necessarily prevent joint destruction or deformity. Rheumatoid arthritis requires medications other than NSAIDs and corticosteroids to stop progressive damage to cartilage, bone, and adjacent soft tissues. These second lines or slow acting or disease modifying antirheumatic drugs may take weeks to months to become effective. They are used for long periods of time, even years, at varying doses. Sometimes a number of DMARD second-line medications are used together as combination therapy. DMARDs are immunosuppressant and they are associated with some common side effects like, skin rash, sore mouth, kidney damage with leakage of protein in the urine, and bone marrow damage with anemia and low white cell count, fever, chills, a metallic taste in the mouth, stomach upset, and easy bruising .
Table 2.DMARDs and Biological response modifiers with their mechanism of actions
ChloroquineÂ and Hydroxychloroquine (Ploquenil) (antimalarials)
Suppression of IL-1 & TNF-Î± induce apoptosis of inflammatory cells and increase chemotactic factors
Aurothiomalate (Myochrysine), Thioglucose (Solganal), Auranofin (Ridaura)
Inhibits macrophage activation
Purine synthesis inhibitor
Cyclosporin A (Sundimmun)
Reducing numbers ofÂ T-lymphocytes
Pyrimidine synthesis inhibitor
Minocycline (Dynacin, Minocin)
BIOLOGICAL RESPONSE MODIFIER
Etanercept (Enbrel), Golimumab (Simponi), Adalimumab (Humira), Infliximab(Remicade)
Anakinra (Kineret), Canakinumab (Llaris)
Basiliximab (Simulect), Daclizumab (Zenapex)
Chimeric monoclonal antibody againstÂ CD20Â on B cell surface
Antibody against CD3 on T cell
Antibody against CD4 on T cell
Antibody against RANKL
Biological agents are biological response modifiers (BRMs). BRMs are specific antibodies against the inflammatory agents responsible for production of pain in RA. They alter the response produced by inflammatory agents and thus reduce pain more effectively and more specifically. BRMs are effective in reduction of pain associated with RA but they have some serious side effects like redness, irritation and increased risk of infection; may be associated with multiple sclerosis-like reactions and possibly, increased risk of lymphoma .
4.1.3 Natural approaches
Because current treatments for arthritis result in unwanted side effects and tend to be expensive, natural products devoid of such disadvantages and offer a novel opportunity. Agents derived from plants that can modulate the expression of pro-inflammatory signals clearly have potential against arthritis. These include flavonoids, terpenes, quinones, catechins, alkaloids, polyphenols, anthocyanins and anthoxanthins, all of which are known to have anti-inflammatory effects.
Table 3.Molecular targets of natural compounds that have anti arthritic activity [20-30]
Boswellia serrata (Salai guggul)
NF-kB, COX-2, 5-LOX, MMP-9, ICAM-1
Berberis vulgaris (barberry)
NF-kB, COX-2, TNF-a, IL-1b, IL-6
NF-kB, COX-2, TNF-a
NF-kB, COX-2, 5-LOX, TNF-a, IL-1b, IL-6, IL-8, MMPs,
Syzygium aromaticum (cloves)
NF-kB, COX-2, 5-LOX, TNF-a, IL-1b
Commiphora mukul (guggul)
NF-kB, COX-2, MMP-9
Allium cepa (onions)
NF-kB, COX-2, TNF-a, 5-LOX, TNF-a, IL-1b, Ams
Vitis vinifera (red grapes)
NF-kB, COX-2, TNF-a, 5-LOX, AMs
Aspergillus terreus (yeast)
NF-kB, COX-2, MMP-9, AMs
Ocimum sanctum (holy basil)
NF-kB, COX-2, MMP-9
NF-kB, COX-2, MMP-9, ICAM-1
5. Various Approaches for the Treatment of RA
Because of the systemic side effects like bone loss, increased susceptibility to infection, osteoporosis, peptic ulcers and buffalo hump  of orally administered NSAIDs, corticosteroids and DMARDs used to treat RA, special drug delivery systems are required to deliver them to the site of action and designed to provide targeted and controlled drug delivery with minimum side effects. We can incorporate the API in novel drug delivery systems like, SLN (Solid Lipid Nano particles), Nano Lipid Vesicles, Liposomes, Hydro gels, Specially Coated Tablets and Capsules, Pulse Release Tablets, Patches, Depot formation, Controlled release microchip, Polymeric carriers, Resealed erythrosomes, which provides optimum, controlled, effective and targeted drug release profile.
5.1. Oral route
Oral route is the most common and conventional route of drug administration. Most of the drugs used in treatment of RA are administered by oral route. Because of the frequent administration and side effects of orally administered medication following approaches are made for desired release profile like extended release dosage forms.
Extended Release dosage forms fall into one of the following two technologies:
A. Hydrophilic, hydrophobic or inert matrix systems: These consist of a rate controlling Polymer matrix through which the drug is dissolved or dispersed.
B. Reservoir (coated) systems: Where drug-containing core is enclosed within polymer coatings. Depending on the polymer used, two types of reservoir systems are considered
(a) Simple diffusion/erosion systems: Where a drug-containing core is enclosed within hydrophilic and/or water-insoluble polymer coatings. Drug release is achieved by diffusion of the drug through the coating or after the erosion of the polymer coating.
(b) Osmotic systems: Where the drug core is contained within a semi-permeable polymer membrane with a mechanical/laser drilled hole for drug delivery. Drug release is achieved by osmotic pressure generated within the tablet core .
Indomethacin Extended release formulation was developed by pelletization and coating based on principle of micro porous membrane drug delivery using soluble salts . Another innovative approach for oral drug delivery involves use of oral pulsatile drug delivery system which involves liberation of drugs following a programmable lag phase from the time of administration .
Magestrol acetate nano crystal oral suspension has been developed and is under review by US FDA for treatment of cachexia . NSAIDs nowadays are combined with other drugs such as misoprotol and this combination is reported to have beneficial action rather than using NSAIDs alone. ArthrotecÂ® (Diclofenac Sodium and Misoprotol) is example of such combination marketed in U.K by Pharmacia Company. Arthrotec provides good protection against gastric erosion and is proved to be efficacious in arthritis .
Controlled-Release Microchip: The conventional controlled drug release from polymeric materials is in response to specific stimuli such as electric and magnetic fields, ultrasound, light, enzymes. Microchip technology has been applied to achieve pulsatile release of liquid solutions. A solid-state silicon microchip was invented at the Massachusetts Institute of Technology (Cambridge, MA), which incorporates micrometer-scale pumps and flow channels to provide controlled release of single or multiple chemical substances on demand .
5.2. Parenteral route
Parenteral products are exclusive among dosage forms of drugs because they are injected through the skin or mucous membranes into internal body compartments . Despite advantages of parenteral drug administration in RA, this route is not often used due to higher incidences of patient noncompliance and rapid clearance rate of drug. Moreover because of self medication is not possible.
Nanoparticles encapsulating anti-arthritic drugs offer advantages of both targeted as well as sustained drug delivery. Higaki et al studied the therapeutic activity of poly (D, L-lactic/glycolic acid) nanoparticles encapsulating betamethasone sodium phosphate to produce slow release and target delivery after intravenous administration of these nanoparticles .
Self administered injectables are available which are easy to use and provide convenient drug delivery devices that treat RA. HumiraÂ® pen is an auto injection device developed for subcutaneous administration of monoclonal antibody adalimumab which offers advantage over intravenous injection since it is easy to use . SimpleJectâ„¢ is auto-injector system is designed for self-administration of Amgen Inc.'s Kineretâ„¢ drug for rheumatoid arthritis .
Lipid Microspheres are excellent carriers for drug delivery owing to their high stability and safety. It has been shown that lipid microspheres get accumulated well in inflammatory lesions of patients with RA . Microspheres encapsulating fragile drugs not only increases patient comfort and compliance but also releases drug from the encapsulating device at a controlled rate for longer period of time lasting for days to genes, plasmid DNA and therapeutic proteins. Microsphere and liposome can also be used in combination therapy. A combination of methotrexate and monoclonal antibody within liposome is well known example. Drug is encapsulated within liposome and antibody is attached to liposome provides two important functions: controlled and targeted release . The role of parenterally administered liposomes in treating RA has also been established. One of the novel approaches to treat RA involves use of prednisolone phosphate containing TRX- 20 Liposomes, which inhibits cytokines and chemokines production in human fibroblast-like synovial cells .
5.3. Topical route
Topical NSAIDs have been reported to have reduced incidences of systemic side effects like gastric bleeding and peptic ulcer . The feasibility of topical route over parenteral route in treatment of RA has been assessed. Topical methotrexate gel in poloxamer 407 polymer have been found to produce sustained and higher drug levels in muscle tissues beneath the site of administration . Currently anti inflammatory drugs are mainly delivered by transdermal iontophoresis. Iontophoresis is a special method of applying drug to and pushing it through the skin to reach the blood vessels and surrounding deeper tissues by electric transmission. Cannabidiol which is a drug used to treat RA is associated with number of systemic side effects when administered orally, however transdermal delivery of cannabidiol using ethosomes carrier system has been designed and is found to prevent inflammation and edema . Penetration enhancers, vehicles like lipid nano/submicron emulsion and formulation like Oleo Hydrogel play an important role in penetration and absorption of drug in percutaneous drug delivery system.(A)
Apart from oral, parenteral and topical drug delivery systems, several innovative drug delivery approaches in treatment of rheumatoid arthritis have been developed. Hypoxia is a common finding in RA which facilitates delivery of bioreductive drug targeting system as oxygen suppresses release of active drug. Bioreductive drug delivery involves three system viz. quinonelactonization systems, self alkylating system and redox mediated cyclisation. Quinone lactonization system involves reduction of quinine and thereby facilitates release of drug through bond cyclisation. Self alkylating system involves conversion of nucleophile into bioreductive structure to favor intramolecular cyclisation over nucleophilic attack from DNA molecules .
Intranasal route of drug administration provides accurate, effective, repeatable and hygienic dosing. Moreover devices used to deliver drug through intranasal route are easy to use and are in pre-filled dose format. Drugs can be given both for local use as well as systemic use through nasal route. . Intranasal administration of human cartilage glycoprotein-39 has been shown to reduce sign and symptoms of arthritis in mouse model .
A number of approaches have been employed to alter the pharmacokinetics of systemically administered compounds so as to improve their therapeutic index. The simplest of these is direct conjugation of a drug to another large molecule. Examples of such drugs currently available are the PEGylated soluble Tumor Necrosis Factor (TNF) receptor and an anti-TNF antibody, which have both shown cheering results in the treatment of RA. Further, RA is characterized by synovial proliferation with chronic inflammatory cell infiltration and new vessel formation . Thus neoangiogenesis strategy seems to be successful in RA. The newly formed vessels show substantially enhanced permeability to macromolecules . This has been successfully exploited in the use of macromolecules to target therapeutic compounds to synovial tissue. For example: Methotrexate (MTX). Also, active uptake of albumin is rapid by synovial fibroblasts [53, 54]. Thus radiolabelled albumin-MTX conjugate is significantly more effective than MTX alone for both, treatment and prophylaxis of collagen induced arthritis. Another well established strategy for the improvement of drug pharmacokinetics and tissue delivery is encapsulation in liposomes.
As in RA there is an increased production of VEGF, vascular Endothelium is an attractive therapeutic target in RA. Therapeutic blockade of angiogenesis has been shown to be efficacious in preclinical models of arthritis. An important molecule that is expressed at low levels by normal endothelial cells but up-regulated in neoangiogenic vessels is the Î±Î³Î²3 integrin, a dimeric transmembrane molecule which binds naturally occurring Arg-Gly-Asp (RGD) sequences in a number of components of the extracellular matrix, including vitronectin, fibronectin, and fibrinogen . Targeting of Î±Î³Î²3 integrin has been shown to enhance the drug delivery. The Folic acid receptor FRÎ² is up-regulated on activated synovial macrophages in a rat arthritis model . Thus specific targeting of Liposomes has been shown to be effective in arthritis and represents an important step forward towards enhancement of efficiency of drug delivery.
Studies involving various types of the connective tissue collagen are in progress and show encouraging signs of reducing rheumatoid disease activity. Finally, genetic research and engineering is likely to bring forth many new avenues for earlier diagnosis and accurate treatment in the near future. Gene profiling, also known as gene array analysis, is being identified as a helpful method of defining which people will respond to which medications. Studies are under way that is using gene array analysis to determine which patients will be at more risk for more aggressive disease. This is all occurring because of improvements in technology.
Pharmacological therapy is the cornerstone in the management of established RA. Pharmacological and non-pharmacological therapies are necessary to reach these goals. This management plan may be adjusted during patient follow-up using information from measurements of disease activity, disability and joint damage. The ability of the new biological response modifiers to intervene in the disease process has generated enthusiasm for therapeutic interventions and for the possibility of future drugs that target individual inflammatory pathways. However, this excitement is tempered by the potential for long-term side-effects and toxicity.
Generally, MTX is regarded as the first choice in the DMARD, and MTX is most often used in combination strategies. Combinations of MTX and TNF blocking agents and MTX with sulphasalazine and/or hydroxychloroquine have shown good efficacy/toxicity ratios. Intramuscular gold, have also been shown to be effective in clinical trials. For optimal treatment in clinical practice, a longitudinal management plan should be defined for each individual patient with established RA, including the goals of treatment. However, it is difficult to predict how patients will respond to first line and second line therapy. Patients not responding to initial therapy are candidates for therapy change including combination strategies.