Raul Soto-Velez1, BSME
1 MS Biotechnology and Bioinformatics program, California State University Channel Islands, Camarillo, California
Rheumatoid arthritis (RA) is a chronic, systemic, progressive autoimmune disease [Choy, 2001][Dudler, 2011][Shin 2009][Hekmat, 2011], characterized by the symmetrical inflammation of the synovial lining of the small joints of the hands, wrists, feet, and knees [Rasch, et at. 2003] [Shiel, 2011]. It is the most common type of inflammatory arthritis [Firestein, 2003]. The disease ultimately leads to the destruction of the cartilage, erosion of the bone, and deformities in joints [Moreland 1999][Shin 2009]. At its most advanced stage, rheumatoid arthritis leads to loss of functionality of the joints [Dudler, 2011].
Various cell types are involved in the initiation and progression of rheumatoid arthritis, among them B cells [Bokarewa, 2007], T cells [Firestein, 2003], macrophages [Boilard 2010], mast cells [Shin, 2009], and platelets [Boilard 2011]. Various signaling molecules are also involved in the mechanisms of disease, including inflammatory and destructive mediators such as cytokines, prostaglandines, and metalloproteinases [Bresnihan, 1998].
Two cytokines in particular, tumor necrosis factor alpha (TNFα) and interleukin – 1 beta (IL-1β) have been found to be the main players in the biochemical pathways that cause inflammation and cell death in rheumatoid arthritis [Bresnihan, 1998]. Other cytokines involved in rheumatoid arthritis are interleukin-6, interleukin-10, interleukin-4 [Choy, 2001], and interleukin-17 [Chabaud, 1998][Kotake, 1999]. Other cytokines such as interleukin-23/17A are expressed in limited amounts in patients with advanced rheumatoid arthritis, but do not have a large role in the disease [Hillyer, 2009].
Demographics and Social Impact
Rheumatoid arthritis is the most common of all inflammatory arthritides [Lawrence, 2008]. It occurs in approximately 0.5 % – 1.0 % of the world’s population [Lundkvist, 2008], and in approximately 2% of people aged 60 or above [Rasch, 2003] in the United States.
Prevalence of rheumatoid arthritis appears to increase with age [Lundkvist, 2008]; in the United States, for people aged between sixty and sixty nine years, prevalence has been estimated to be between 1.59% - 1.89%; while for people aged sixty years or older, it has been estimated to be between 2.46% - 2.80% [Rasch, 2003].
Rheumatoid arthritis has significant social and personal costs [Choy, 2001]. Patient’s life expectancy is reduced by between three and eighteen years [Choy, 2001]. Presently there is no cure for rheumatoid arthritis [Choy, 2001] [Dudler 2011]. Within twenty years, 80% of rheumatoid arthritis patients are disabled and unable to work [Choy, 2001].
Genetic factors appear to have an important role in the susceptibility to rheumatoid arthritis, and a number of genes have been identified as related to the pathogenesis of the disease and as potential targets for treatments [Perricone, 2011]. In the United States, Mexican-Americans have a higher rate of rheumatoid arthritis that non-Hispanic whites, while African Americans have a lower rate [Rasch, 2003]. The prevalence of rheumatoid arthritis in women is approximately 150% higher than in men [Rasch, 2003].
The social and economic costs of rheumatoid arthritis have been estimated to be approximately 41.6 billion euros (US $59.94 billion) in the United States, and 45.30 billion euros (US $65.27 billion) in Europe [Lundkvist, 2008].
A new classification criteria, which provides specific guidelines for the diagnosis of rheumatoid arthritis, was published in August 2010 [Kaneko, 2011].
A combination of various diagnostic methods is used to diagnose rheumatoid arthritis [Shiel, 2011]. Blood tests are typically done to perform immunological assays that detect the presence of antibodies associated with rheumatoid arthritis; such as rheumatoid factor (RF), antibodies to cyclic citrullinated peptides (anti-CCP) [Schellekens, et al, 2000], and antinuclear antibody (ANA) [Shiel, 2011]. Other blood tests commonly used in the diagnosis of rheumatoid arthritis are the elevated erythrocyte sedimentation rate (ESR) test; and testing for the presence of C-reactive protein, which correlates to inflammation in the body [Shiel, 2011].
Radiography (X-rays) is commonly used to follow the progress of the disease by monitoring the erosion of the joint bones and the inflammation of soft tissue in the joints [Shiel, 2011].
Magnetic resonance imaging (MRI) has also been investigated as a diagnostic tool for early detection rheumatoid arthritis [Suter, 2010]. Magnetic resonance imaging is able to detect erosion in the joint bones and inflammation in the synovium at an earlier stage than X-Rays [Suter, 2010].
Mechanism of Disease
Figure 1 shows a comparison of a healthy joint against a joint afflicted with rheumatoid arthritis.
The inflammatory process is normally regulated by mediators that initiate the inflammatory response and mediators that inhibit it [Choy 2001]. In rheumatoid arthritis patients these regulators are not balanced, which allows an increase in inflammation that leads to tissue damage and destruction [Choy 2001].
In a normal, healthy joint, a layer of cartilage tissue covers and protects the ends of the bones, surrounded by a synovial membrane which consists of a layer one or two cells thick [Choy, 2001] and which holds the synovial fluid that lubricates and nurtures cartilage tissue [Lee, 2007].
In a joint with early rheumatoid arthritis, the synovial membrane becomes inflammated and thickens due to hyperplasia and hypertrophy of the cells that line the synovium, and begins to invade the cartilage tissue [Choy, 2001]. The synovial membrane is infiltrated by T cells and B cells [Choy, 2001].
When rheumatoid arthritis reaches a more advanced (established) state, the inflammated synovial tissue becomes the pannus, inflammatory tissue that invades and destroys the bone and cartilage in the joint [Choy, 2001].
Figure 1: Pathogenesis of Rheumatoid Arthritis (Choy 2001)
It is not yet known what triggers the immune response that causes the body’s antibodies to attack the cartilage and the synovial membrane [Shiel, 2011]. It is known, however, that increased expression of inflammatory cytokines such as TNF α, IL-1, IL-6, and others has a key role in the inflammatory response and tissue destruction elements of the disease [Egan, 2003].
The mechanisms that control the secretion of cytokines are not completely known [Chaofeng, 2009]. Lymphocytes are attracted to the site where antibodies attack the joint tissues, where they differentiate into macrophages and release cytokines such as tumor necrosis factor α (TNF α), interleukin-1 (IL-1), and interleukin-6 (IL-6) [Shiel, 2011].
TNFα increases the expression of adhesion molecules in endothelial cells, which in turn recruits additional immune cells to the site of the attack, amplifying the immune response [Choy, 2001] [Shiel, 2011]. IL-1 and IL-6 act as signaling molecules, also recruiting more immune cells to the afflicted area [Choy, 2001]. IL-1 is an important mediator of the autoimmune response, bone resorption and cartilage damage in rheumatoid arthritis, although it is not a major mediator in inflammation or joint swelling [Schiff, 2000]. Exposure to IL-1 and TNFα stimulates the expression of IL-6, another inflammatory cytokine [Ishimi, 1990] [Palmqvist, 2002] [Palmqvist, 2008]. TNFα and IL-1β regulate gene expression in microphages and in fibroblast-like synoviocytes, stimulating the expression of cytokines such as IL-6, IL-8, while reducing the expression of IL-17 [Mi Choi, 2010]. The combined effect of all these factors increases the joint damage caused by the degradation of connective tissue [Choy, 2001].
Elevated levels of TNF α and IL-1β have also been found to induce osteoporosis in rheumatoid arthritis patients by up-regulating the apoptosis of osteoblasts [Tsuboi, 1999]. Elevated levels of cytokines such as TNF α and IL-1β have also been linked to Alzheimer’s disease [Tobinick 2008], recurrent ovarian cancer [Madhusudan, 2005], and autoimmune thyroid diseases [Wang, 2007].
In addition to cytokines and monocytes, platelets have also been shown to have a role in rheumatoid arthritis [Boilard 2010]. The regulated synthesis of interleukin 1β by activated platelets mediates inflammatory signaling [Lindemann, 2001]. Adhesion of platelets-neutrophil complexes in vivo contributes to acute inflammatory responses [Kornerup, 2010]. Platelet microparticles, which are submicrometer vesicles generated by activated platelets, have been found to induce the secretion of cytokines such as IL-1 by synovial fibroblasts [Boilard 2010]. Platelet-polymorphonuclear neutrophil (PMN) adhesion has been shown to contribute to inflammation [Pastakia, 1996]. The production of microparticles from the platelet membrane is activated via the collagen receptor GPVI [Boilard 2011]. In rheumatoid arthritis patients, high levels of microparticles in the synovial fluid stimulate the production of IL-1, thus increasing joint inflammation [Boilard 2011]. Research has shown that a raised platelet count is correlated to rheumatoid arthritis [Farr, 1983] and that this can be used to create functional assays that monitor disease activity [Gyorgy, 2011].
Platelets can also induce inflammatory responses in the synovial membrane of the joints in rheumatoid arthritis patients by a separate pathway that does not involve microparticles [Boilard, 2011]. Platelets interact with collagen and become activated by means of the platelet collagen receptor Glycoprotein IV [Smethurst, 2006]. Activated platelets express cyclooxygenase-1 (COX-1), which increases the paracrine production of prostacyclin in fibroblast-like cells called synoviocytes [Boilard, 2011].
The TNFα / NF-kB Biochemical Pathway
Tumor Necrosis Factor alpha (TNFα), a cytokine secreted by macrophages and monocytes, has been found to mediate the inflammatory response and the activation of apoptosis in cells in rheumatoid arthritis, among other diseases [Chen, 2002][ Baumgartner, 2000]. In rheumatoid arthritis patients, high levels of TNFα can be found in the synovial fluid, synovial tissue, and in the cartilage-pannus junction [Baumgartner, 2000]. IL-1 release triggered by TNFα has been linked experimentally to decreases in patient’s cognitive abilities [Terrando, 2010].
It is known that cytokines binding to transmembrane receptors causes an increase of tyrosine phosphorylation, which in turn triggers the activation of signal transduction pathways [Bracke, 1998]. TNFα interacts with two membrane-bound receptors, TNF-R1 and TNF-R2, with TNF-R1 being the one involved in the most important biochemical pathway for rheumatoid arthritis, the TNFα / NF-kB signal transduction pathway [Chen, 2002][Locksley, 2001].
When TNFα binds to TNF-R1, it activates a signal transduction pathway that leads to the activation of transcription factors NF-kB and c-Jun, which are involved in the transcription of genes related to cell death, immunological and inflammatory responses, and cancer, among others (Chen, 2002). Figure 2 illustrates the signal transduction pathway for TNFα / NF-kB.
When TNFα binds to the TNF-R1 membrane-bound receptor, the intra-cellular domain of the TNF-R1 receptor releases the SODD (silencer of death domain) inhibitory protein [Chen, 2002]. When this happens, the TNF receptor-associated death domain (TRADD) recognizes the change in the intra-cellular domain of TNF-R1 and recruits adaptor proteins such as receptor-interacting proteins (RIP), which is a protein kinase; TNF-R-associated factor 2 (TRAF2); and Fas-associated death domain (FADD)[Chen, 2002] [Locksley, 2001].
RIP, TRAF2 and FADD in turn recruit enzymes to the intracellular domain of TNF-R1 in order to initiate the signaling cascade [Chen, 2002]. FADD recruits caspase-8, TRAF2 recruits cIAP-1 and CIAP-2, and activates a cascade of kinases that results in the phosphorylation and activation of c-Jun [Chen, 2002].
NF-kB is normally found bound to inhibitor IkB proteins in the cytoplasm, which maintains it inactive [Chen, 2002]. The kinase cascade that phosphorylates and activates c-Jun also causes the phosphorylation and activation of the IKK (IkB kinase) complex, which mediates the phosphorylation of IkB proteins; this in turn causes IkB to disassociate from NF-kB [Chen, 2002]. Once NF-kB is separated from IkB, it becomes activated, and translocated into the nucleus of the cell, where it recruits other transcription factors and expresses genes related to apoptosis (cell death) and the inflammatory response [Chen, 2002].
Figure 2: TNFα / NF-kB signal transduction pathway (Chen, 2002)
NF-kB triggers the inflammatory response by promoting the transcription of genes that express inflammatory cytokines such as interleukin-1 (IL-1a and IL-β) [Dinarello, 1996]. IL-1 activates T-cells and enhances the proliferation of fibroblasts, which in turn causes the formation of the pannus and contributes to the destruction of bone, cartilage and joint tissues [Furst, 2004].
Other Relevant Pathways
Inhibiting the action of TNFα and IL-1 suppresses the symptoms of rheumatoid arthritis in many patients; however, in a large percentage of patients symptoms persist, indicating that there are alternate pathways involved in the mechanism of the disease [Walker, 2005]. In addition to the two platelet-related mechanisms mentioned previously, another pathway that has been proposed and investigated is the Jak-STAT signal transduction pathway [Walker, 2005].
Treatment of Rheumatoid Arthritis
The main purpose of pharmacological treatments for rheumatoid arthritis is to prevent joint damage, reduce the inflammatory response, and improve joint function [Hekmat, 2011].
There are three fundamental ways of inhibiting the biochemical pathways that trigger tissue inflammation and cell apoptosis: neutralizing the action of inflammatory cytokines (keep them from binding with their corresponding transmembrane receptors by binding the cytokines with a soluble receptor, a monoclonal antibody, or a natural antagonist), blocking the transmembrane receptors for inflammatory cytokines (use a receptor antagonist or a monoclonal antibody to bind to the receptor and blocking the cytokine from binding), and activating pathways that will express anti-inflammatory cytokines such as IL-4 or IL-10, which inhibit the expression of inflammatory cytokines [Chen, 2002].
On in-vitro studies performed on synovial cells from rheumatoid arthritis patients, inhibiting the action of TNFα had the effect of reducing the production of cytokines associated with inflammatory responses, such as IL-1, IL-6, and IL-8, among others [Chen, 2002]. This key role of TNFα makes it a prime target for drugs that inhibit its effect [Chen, 2002]. The TNF-R2 receptor fused with the human IgG1 Fc region has also been used to treat rheumatoid arthritis, but it is not as effective as other antibodies against cells with TNF on the cell surface [Nagashima 2011].
There are three main types of drugs used to treat rheumatoid arthritis: NSAIDs, DMARDs, and biologics [Shiel, 2011]. These are frequently used in combinations for best effect [Shiel, 2011]. In this paper, we will provide a general description of NSAIDs and DMARDs, and will focus on biologics and their mechanisms of action at the molecular level. This paper will further focus on the four biologic treatments most widely used against rheumatoid arthritis: Enbrel (Etanecerpt), Humira (Adalimumab), Kineret (Anakinra), and Remicade (Infliximab) [Cush, 2010].
The first class of drugs used to treat rheumatoid arthritis are Non Specific Anti-Inflammation Drugs (NSAIDs) [Shiel , 2011]. NSAIDs are fast-acting drugs that treat the symptoms of rheumatoid arthritis such as pain, swelling, and inflammation [Shiel, 2011]. NSAIDs do not alter the course of the disease or slow down the progression of joint destruction [Shiel, 2011].
NSAIDs act as cyclooxygenase (Cox-1 and Cox-2) inhibitors [Silverstein, 2000]. These cyclooxygenase enzymes play a key role in the production of prostaglandines; by inhibiting their actions, NSAIDs reduce swelling and pain [Silverstein, 2000]. Cox-1 inhibition also causes gastrointestinal toxic effects, such as ulcers [Silverstein, 2000]. Celecoxib, which is a Cox-2- specific inhibitor, has been shown experimentally to cause lower gastrointestinal toxic effects than ibuprofen [Silverstein, 2000]. Table 1 lists the most commonly used NSAIDs.
Advil, Medipren, Motrin
Cox-2 inhibitors, such as Celecoxib
Table 1 : NSAIDs used in the treatment of rheumatoid arthritis (Shiel, 2011)
The second class of drugs used to treat rheumatoid arthritis are Disease Modifying Anti Rheumatoid Drugs (DMARD) [Shiel, 2011]. DMARDs slow down the progression of the disease, but they act slower than NSAIDs; their effect becomes observable weeks or months after the patient starts to take them [Shiel, 2011]. Table 2 lists the most commonly used DMARDs.
A research study performed by Mottonen, et al  compared combination therapies consisting of various DMARDs such as sulphasalazine, methotrexate, hydroxy-chloroquine, and prednisolone, against a single-drug therapy. Combination therapy showed significant improvements in swollen joint count over the single-drug treatment [Mottonen, 1999]. In some patients, however, DMARDs do not attain satisfactory responses due to toxicity [Moreland, 1999].
Another research study, performed by Cohen  compared the effects of treating rheumatoid arthritis with leflunomide against the effects using methotrexate, in a two-year-long, randomized, controlled clinical trial. Both treatments slowed down the progression of the disease, with leflunomide showing better results than methotrexate [Cohen, 2001].
A more recent research study performed by DeStefano  compared combination therapies of leflunomide plus an anti-TNFα biologic against methotrexate plus an anti- TNFα biologic. The study shows that both DMARDs can be used safely in combination with anti- TNFα biologics [DeStefano, 2010].
Gold salts such as
Oral gold, auranofin
Table 2 : DMARDs used in the treatment of rheumatoid arthritis (Shiel, 2011)
Biologic treatments for Rheumatoid Arthritis
A third class of drugs used to treat rheumatoid arthritis are Biologics. While DMARDs are non-specific anti-inflammation drugs that target the immune system in a general way [Shiel, 2011], most biologics target specific cell surface markers or specific signaling molecules to inhibit their action and prevent the triggering of biochemical pathways that lead to inflammation responses and apoptosis [Rasheed 2008]. Table 3 lists various biologic drugs used to treat rheumatoid arthritis.
The current treatment approach is to combine use of DMARDs and biologics at the early stages of the disease to achieve complete remission [Dudler, 2011]. Klareskog  compared a combined treatment of rheumatoid arthritis patients using etanercept and methotrexate (DMARD) against treatment with each alone, using a double-blind randomized trial. The combined treatment reduced symptoms, improved patient’s functional disabilities, and slowed down the disease’s progression. [Klareskog, 2004].
Table 3 : Biologics used in the treatment of rheumatoid arthritis (Cush, 2010)
A study performed by Graudal, et al  in the Netherlands showed that biologics, glucocorticoids, DMARDs, and combined agents had similar effects on patients after one year of treatment; which led these researchers to recommend that biologics should be used only for patients that are not responsive to DMARDs treatments [Graudal, 2010].
Combination therapy using multiple biologic drugs has not demonstrated any synergistic effects; in a study that combined the use of Etanercept, a TNFα inhibitor, with Anakinra, an IL-1 inhibitor, patients did not gain any additional benefits, while the risk of serious infections increased significantly [Genovese, 2004].
As mentioned previously, this paper will focus on the four biologic treatments most widely used against rheumatoid arthritis: Enbrel (Etanecerpt), Humira (Adalimumab), Kineret (Anakinra), and Remicade (Infliximab) [Cush, 2010].
Etanercept , which is sold under the commercial name Enbrel, is a recombinant dimeric fusion protein, which combines the human gene for the extracellular ligand-binding domain of two human soluble TNFα type-II receptors with the gene for the Fc (fragment crystallizable) component of human immunoglobulin G1 (IgG1) [Tobinick 2008] [Wikipedia: Etanercept, 2011]. It inhibits TNFα by binding to it, which prevents it from binding to transmembrane receptors [Cush, 2010]. It has a half life of 5 days [Cush, 2010]. Effects on most patients can be seen 2 - 4 weeks after the treatment begins [Cush, 2010]. Figure 3 shows how soluble receptors such as Enbrel bind to cytokines to inhibit their action.
The most common adverse effects observed in Enbrel patients are injection site reactions such as skin irritation, and upper respiratory infections such as cold, sinusitis, or bronchitis [Cush, 2010]. Less common adverse effects observed are bacterial infections, optic neuritis, multiple sclerosis, nerve disorders, and heart failure [Cush, 2010].
Figure 3: Inhibition of Cytokines by binding with monoclonal antibodies or soluble receptors (Choy, 2001).
Enbrel is administered by subcutaneous injection, once or twice per week [Cush, 2010]. FDA prescription guidelines do not require using methotrexate along with Enbrel [Cush, 2010]. The dose is 50 mg weekly, or 25 mg twice per week [Cush, 2010]. The estimated annual cost of treatment is $15,436 [Cush, 2010].
In clinical trials, Enbrel has been shown to reduce symptoms of rheumatoid arthritis, to slow down the progression of joint damage, and to improve the general quality of life in patients [Moreland, 1999][Haraoui 2007]. A clinical trial was performed by Johnsen, et al  to determine the effects of a dosing regimen of 50 mg twice weekly, twice the current regime. No increase in effect or benefits to patients were observed at the higher dose, when compared to the current dose [Johnsen, 2006].
Etanercept has also been evaluated as a treatment for Alzheimer’s disease [Tobinick 2008] and recurrent ovarian cancer [Madhusudan, 2005]. Excessive amounts of TNFα, which has been found to regulate synaptic functions in neural networks, have been linked to Alzheimer’s disease [Tobinick 2006]. Alzheimer’s patients treated with Enbrel showed rapid cognitive improvements within minutes of receiving the drug [Tobinick 2008]. TNFα , as a major mediator of inflammation, is produced chronically in ovarian tumors, and the increase in cytokine production triggered by TNFα is believed to assist in tumor growth [Madhusudan, 2005]. The Madhusudan study found evidence of biological activity of etanercept against ovarian cancer, and recommended further research [Madhusudan, 2005].
Adalimumab , which is sold under the commercial name Humira, is a fully-human monoclonal antibody [Wikipedia: Adalimumab, 2011] that binds to TNFα and inhibits it from binding to transmembrane receptors. [Cush, 2010]. It has a half life of 12-14 days [Cush, 2010]. Effects on most patients can be seen 2 - 4 weeks after the treatment begins [Cush, 2010]. Figure 3 shows how monoclonal antibodies bind to cytokines to inhibit their action.
The most common adverse effects observed in Humira patients are similar to those observed in Enbrel patients: injection site reactions such as skin irritation, and upper respiratory infections such as cold, sinusitis, or bronchitis [Cush, 2010]. Less common adverse effects observed are bacterial infections, optic neuritis, multiple sclerosis, nerve disorders, and heart failure [Cush, 2010].
Humira is administered by subcutaneous injection, every other week [Cush, 2010]. FDA prescription guidelines suggest using methotrexate along with Humira [Cush, 2010]. The dose is 40 mg once every two weeks[Cush, 2010]. The estimated annual cost of treatment is $14,522 [Cush, 2010].
In clinical trials, Adalimumab has been shown to be safe and effective in the treatment of rheumatoid arthritis and other inflammatory conditions both in monotherapy [van de Putte, 2003], and in combination therapy with methotrexate [Breedveld, 2006][Weinblatt, 2003]. Combination therapy was found to be more effective than monotherapy [Breedveld, 2006].
Anakinra, which is sold under the commercial name Kineret, is a receptor antagonist [Wikipedia: Anakinra, 2011] [Furst, 2004] that inhibits the effect of Interleukin-1 (IL-1) by competitively inhibiting the binding of IL-1 to the IL-1 transmembrane receptors [Schiff, 2000][Cush, 2010]. It has a half life of 6 hours [Cush, 2010]. Effects on most patients can be seen 4 - 6 weeks after the treatment begins [Cush, 2010]. Figure 4 shows how receptor antagonists such as Anakinra bind to transmembrane receptors to inhibit the action of cytokines.
The most common adverse effects observed in Kineret patients are similar to those observed in Enbrel and Humira patients: injection site reactions such as skin irritation, and upper respiratory infections such as cold, sinusitis, or bronchitis [Cush, 2010]. Headaches are also a common adverse effect of Kineret, not observed in other biologics [Cush, 2010]. Less common adverse effects observed are pneumonia, skin or joint infections, and very low white blood cell counts [Cush, 2010].
Kineret is administered by subcutaneous injection, daily [Cush, 2010]. FDA prescription guidelines do not require using methotrexate along with Kineret [Cush, 2010]. The dose is 100 mg daily [Cush, 2010]. The estimated annual cost of treatment is $12,800 [Cush, 2010].
Figure 4: Blocking of transmembrane receptors by binding with monoclonal antibodies or receptor antagonists (Choy, 2001)
In clinical trials, Anakinra has been shown to be mildly to moderately effective in reducing symptoms of active rheumatoid arthritis in patients, both in monotherapy [Fleischmann, 2003] and combined with methotrexate [Furst, 2004].
Infliximab, which is sold under the commercial name Remicade, is a mouse-human chimeric antibody [Wikipedia: Remicade, 2011] that inhibits the action of TNFα by binding to it [Cush, 2010]. It has a half life of 9 days [Cush, 2010]. Effects on most patients can be seen 2 - 4 weeks after the treatment begins [Cush, 2010]. Figure 3 shows how monoclonal antibodies bind to cytokines to inhibit their action.
The most common adverse effects observed in Remicade patients are infusion reactions such as itching, rash, nausea, and headaches; and upper respiratory infections such as cold, bronchitis, and sinusitis [Cush, 2010]. Less common adverse effects observed are anaphylaxis; opportunistic bacterial infections such as pneumonia or joint infections; tuberculosis; fungal infections; nerve disorders such as optic neuritis and multiple sclerosis; and worsening of heart failure [Cush, 2010].
Unlike Enbrel, Kineret or Humira, which are self-administered by subcutaneous injection, Remicade is administered by intravenous infusion in the clinic or doctor's office, every 8 weeks [Cush, 2010]. FDA prescription guidelines require using methotrexate along with Remicade [Cush, 2010]. The initial dose is 3 - 5 mg/kg at weeks 0, 2, and 6; and if necessary this dose can be increased to 5 - 10 mg/kg [Cush, 2010]. Maintenance doses are required every 4 - 8 weeks [Cush, 2010]. The estimated annual cost of treatment is between $13,940 and $30,287 [Cush, 2010].
Clinical trials have compared monotherapy with Infliximab against monotherapy with methotrexate, and against a combined therapy of both Infliximab and methotrexate [StClair, 2004][Maini, 1998]. It was found that the combined therapy is more effective than monotherapy with either drug alone [StClair, 2004] [Maini, 1998]. However, other studies in Infliximab patients showed poor response, prompting the physicians to switch patients to other treatments [Mori 2011].
According to ClinicalTrials.gov, a website maintained by the National Institutes of Health (NIH), there are eleven drugs for the treatment of rheumatoid arthritis currently undergoing clinical trials; as shown in Table 4.
Biological: Certolizumab Pegol
University of Michigan / NIH
Baylor Research Institute
Imperial College London
Cura Biotech LLC
Table 4 : Rheumatoid drugs currently in clinical trials
Laliumab, which will be sold under the commercial name Jazireum®, is a fully human monoclonal antibody that treats autoimmune disease by blocking the active site of the Tumor Necrosis Factor Receptor-1 (TNF-R1) transmembrane protein. Figure 5 shows a computer rendition of the Lalitumab protein molecule model, obtained using X-Ray crystallography, WinCoot, and Swiss PDB Viewer.
Figure 5: Laliumab (Jazireum®), a fully human monoclonal antibody
Mechanism of Action
Laliumab disrupts the interaction between TNFα and the TNF-R1 transmembrane receptor by blocking the active site of the receptor, and thus inhibiting TNFα from binding. By binding competitively with the TNF-R1 receptor (Figure 6), Laliumab prevents the formation of the TNFα-TNF R1 complex, and this in turn prevents the triggering of the pathway which produces cell necrosis and inflammation in rheumatoid arthritis and other autoimmune diseases.
As with other anti-TNFα biologics, the main adverse events associated with Laliumab are injection site reactions such as irritated skin, and opportunistic infections in the respiratory tract, such as cold, sinusitis, and bronchitis.
Less common adverse events are also similar to those caused by other anti- TNFα biologics: opportunistic bacterial infections; nerve disorders such as seizures, multiple sclerosis, and eye nerve inflammation; psoriasis; allergic reactions; autoimmune reactions; and heart failure.
Formulation, Dose, and Cost Estimate
Laliumab is self-administered by subcutaneous injection. It is available in two dosage options: a 50 mg/mL autoinjector, and a 50 mg single-use prefilled syringe.
Laliumab has a half-life of approximately 12-14 days. Most patients will begin to feel effects within 2 – 4 weeks after the start of the treatment. FDA prescription guidelines suggest using Laliumab along with methotrexate for optimal effect. The estimated annual cost of treatment is $15,000.
Figure 6: Laliumab blocks the action of TNFaby binding to the TNF-R1 receptor active site
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