Given the recent advances in the understanding of rheumatoid arthritis, these authors offer a closer look at the pathogenesis of the disease and the potential impact of biologic therapies.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects more than 2 million Americans. It is associated with intense pain, irreversible joint destruction, systemic complications and a progressive functional decline. The disease is also associated with a decreased life expectancy of five to 15 years secondary to comorbid illnesses that may be exacerbated by the underlying pathophysiologic mechanisms.1

In the past, clinicians were seldom able to achieve satisfactory remission of RA so therapy was more focused on controlling joint damage and pain with preservation of joint mobility. Back then, healthcare professionals would be satisfied to make a diagnosis of RA based on watchful waiting for months and utilizing a therapeutic pyramid approach beginning with non-steroidal antiinflammatory drugs (NSAIDs) as the therapeutic foundation. Not only were there limited treatment options, there was limited clinical data on the risks and benefits of disease-modifying anti-rheumatic drugs (DMARDs). The use of DMARDs was restricted to patients who had evidence of advanced disease progression.

When it comes to rheumatoid arthritis, negative effects on the quality of life include pain associated with functional disability, chronic severe fatigue, depression and loss of job productivity.

However, during the 1990s, a number of clinical studies established the effectiveness of DMARDs and the impressive utility of interventions involving biologic agents.1,2 These findings emphasized the need for early, aggressive treatment and encourage us to believe that we are now in a strategic position to significantly reduce the burden of RA.

Accordingly, let us take a closer look at recent advances in our understanding of the molecular basis of RA and its therapeutic implications.

Recognizing The Signs Of Early RA And Advanced RA
Rheumatoid arthritis is the most common systemic inflammatory arthritis seen in primary care. It is a chronic, progressive inflammatory disease of unknown etiology that can lead to permanent destruction of synovial joints with loss of cartilage and bone. There is also damage to ligaments and tendons that results in loss of physical function and a diminished quality of life. Systemic symptoms and signs — which can predate the onset of joint symptoms — include fatigue, weakness, depression and unexplained weight loss.

The prevalence of RA ranges from 0.5 to 1.5 percent. Rheumatoid arthritis is 2.5 times more common in women than in men. In most patients (about 70 percent), the onset is insidious. The metacarpophalangeal (MCP), proximal interphalangeal (PIP) and metatarsophalangeal (MTP) joints are usually involved before the larger joints. Other less common presentations include persistent monoarthritis and palindromic or polymyalgic onset.1

In the early stage of RA, the disease affects the synovial membranes and periarticular structure of multiple joints, which results in swelling, pain and inflammation. Tenderness and limited range of motion are common in the MCP and PIP joints. No destructive changes are visible on radiographs at this stage. Patients with moderate RA typically have diffuse swelling and limited joint mobility without joint deformities. Extraarticular nodules and tenosynovitis may develop. Radiographic findings include periarticular osteopenia and minor cartilage destruction.

Advanced RA is characterized by severe cartilage and bone destruction (such as marginal joint erosions) that result in joint deformity (i.e. subluxation, ulnar deviation and bony ankylosis). Inflammatory joint symptoms appear to be the main determinants of disability early in the disease while joint destruction dominates later in the disease.

Cartilage-destroying mechanisms that produce joint destruction are activated very early in the course of the disease. Up to 93 percent of patients who have had RA for less than two years may have radiographic abnormalities. Some patients with a four-month history of symptoms and normal radiographs have joint erosions that are detectable on MRI. Joint erosions are identified by radiographic progression.1

The systemic consequences of RA may also be severe. Multiple organ systems may be involved. Patients with RA have an approximately 30 percent higher early mortality than the general population. They are also twice as likely to suffer a myocardial infarction and are significantly more likely to develop a stroke or infection. They are also at increased risk for lymphoma. Negative effects on quality of life include pain associated with functional disability, chronic severe fatigue, depression and loss of job productivity.1

Understanding The Pathogenesis Of Rheumatoid Arthritis
Rheumatoid arthritis is an immune-mediated disease that develops in a genetically predisposed host. It is characterized by development of a hyperplastic synovial membrane (i.e. pannus) that has been infiltrated by B-cells and macrophages, which lead to the production and release of proinflammatory cytokines. These events result in further localized and systemic inflammation, leading to synoviocyte, chondrocyte and osteoclast activation, and cartilage and bone destruction.

In diseases such as RA, an imbalance develops between the proinflammatory cytokines (i.e. interleukin (IL)-1b, tumor necrosis factor-a (TNF-a, IL-6, IL-15)) and the antiinflammatory cytokines (i.e., soluble TNF receptors, IL-1 receptor antagonists).

While there are numerous other cytokines in the RA synovial tissue or fluid, TNF and IL-1 appear to play dominant roles. Since TNF triggers production of many other cytokines, including IL-1, researchers have generally viewed this cytokine as pivotal in initiating the inflammatory response that causes cartilage and bone destruction, and other systemic events. Targeting TNF has proved to be very successful in the treatment of RA while targeting IL-1 has been most successful in treating RA patients who had an inadequate response to TNF antagonists.

Assessing The Impact of DMARDs
Important studies to date have provided evidence of the following tenets in treating RA.

• NSAIDs/COX-2 inhibitors do not prevent joint destruction.
• Treatment with methotrexate or low dose corticosteroids slows the progression of RA.
• Combination DMARD treatment slows the progression of erosive disease.
• The use of biologic antagonists markedly reduces rheumatoid inflammation.
• DMARDs, and especially TNF antagonists, are effective in retarding joint destruction.
• Damage to joints occurs very early and is progressive.
• Inflammatory symptoms do not correlate with joint destruction.
• Early DMARD intervention leads to better long-term outcomes.
• Early and combination therapy leads to the best outcomes.
• There is a window of opportunity for highly successful treatment of RA, especially in the first three months of therapy.1

Based on the above conclusions from studies, early diagnosis and DMARD biologic therapy have become essential in achieving optimal patient outcomes including retarding disease progression. Disease-modifying anti-rheumatic agents, such as methotrexate, sulfasalazine, leflunomide and, most recently, TNF antagonists, not only control signs and symptoms of RA but also retard disease progression, improve function and enhance one’s quality of life. With the development of these agents, the focus of RA treatment has now clearly shifted from management of constitutional symptoms to changing the course of the disease.2

A Pertinent Primer On TNF Antagonists
The introduction of biologic agents, such as TNF antagonists, into clinical practice has had a profound effect on the current management of RA. The ability of these agents to rapidly enhance functional status and inhibit progression of joint damage has been exceptional. To date, nearly one million patients worldwide have received one of the three TNF antagonists currently available: etanercept (Enbrel, Amgen/Wyeth), infliximab (Remicade, Centocor), and adalimumab (Humira, Abbott).3-10

The inflammatory cytokine TNF-a is found in high concentration in inflamed joints in patients with RA. As we mentioned earlier, TNF-a produces several proinflammatory effects that contribute to joint destruction. It stimulates the release of other proinflammatory cytokines, promotes leukocyte migration, activates neutrophil and eosinophil functional activity and induces tissue-degrading enzymes produced by synoviocytes and chondrocytes.

Approved by the FDA in December 2005, abatacept (Orencia) is indicated for patients with RA who have had an inadequate response to TNF Antagonists at any stage of the disease.

Etanercept is a fusion protein that consists of the ligand-binding region of the human TNF-a receptor linked to the Fc portion of human IgG1. It has a half-life of three to five and a half days. It is indicated for the treatment of moderate to severe RA, alone or in combination with methotrexate, at a dose of 50 mg once weekly or 25 mg twice per week by subcutaneous injection.

Infliximab is an anti-TNF-a chimeric antibody that inhibits binding of TNF-a to its receptors. It has a half-life of eight to 10 days. It is indicated for the treatment of moderate to severe RA at an infusion rate of 3 to 10 mg/kg over two hours, once every four to eight weeks, in combination with methotrexate. In a recent study that evaluated whether one can taper infliximab without RA flare, 52 percent of the patients were able to discontinue their infliximab and taper methotrexate with good clinical response for periods of months.9 This suggests that one can achieve an extended remission in some patients with the use of TNF antagonists.

Adalimumab, a recombinant human IgG1 monoclonal antibody specific for human TNF-a, inhibits binding of TNF-a to both of its receptors and lyses cells that bear TNF-a on their surfaces. It does not bind or inactivate lymphotoxin (TNF-b). Adalimumab has a half-life of 10 to 20 days. It is indicated for use alone or with other DMARDs in patients with moderate to severe RA. One can administer this medication at a dose of 40 mg every two weeks via subcutaneous injection.9

An additional biologic agent, anakinra (Kineret, Amgen), blocks the biologic activity of naturally occurring IL-1-beta by competitively inhibiting the binding of IL-1 to the interleukin-1 type I receptor (IL-1RI). This biologic agent is indicated for use in patients with moderate to severe RA, who have not had an adequate response to conventional DMARD therapy. One can use this agent in conjunction with methotrexate or other DMARDs (other than TNF blocking agents) or clinicians can utilize it as a monotherapy. Patients can self-administer anakinra as daily subcutaneous injections using pre-filled 100 mg syringes.11

The safety profile of all of the above biologics has been established. Serious infections and lymphomas are associated with the use of TNF antagonists but the occurrence is rare. It has yet to be defined as to whether concomitant therapies, comorbidities and the activity of RA contribute to the risk of these adverse effects. Clinicians should discuss with their patients the potential risks of all treatments against the potential benefits of these agents, which researchers have shown are significantly effective in treating RA.9,10

Fulfilling The Unmet Needs In RA Therapy: Can Abatacept And Rituximab Have An Impact?
Despite the many therapeutic advances in the treatment of RA, there are still many unmet needs for patients who have had an inadequate response to TNF antagonists. These include patients who fail to achieve substantial clinical response or remission as well as those in which joint damage does not heal secondary to treatment delays that have resulted in irreversible damage. For example, in an extensive registry for biologic use for RA in Sweden, 50 percent of RA patients were partial responders with moderate to high DAS28 after one year. In addition, only 40 percent maintained TNF therapy for five years.12

In order to deal with these issues, two new biologic agents have recently been approved for the treatment of RA in patients who have had an inadequate response to TNF antagonists.

Abatacept (Orencia, Bristol Myers Squibb) is a T-cell inhibitor, soluble fusion protein. It works as a selective co-stimulation modulator that inhibits T-cell activation and accordingly prevents the co-stimulation of a signal that is necessary for a full activation of T-lymphocytes. Approved by the Food And Drug Administration (FDA) in December 2005, abatacept is indicated for patients who have had an inadequate response to TNF antagonists at any stage of the disease.

Controlled clinical trials have shown that optimal dosing of abatacept significantly reduced structural damage progression (including decreased erosions and joint space narrowing) and improved the total joint score. Studies have also shown significant improvements in the quality of life measures, ACR 20, 50 and 70 scores, and DAS28 scores.13-18

Concomitant use of biologic DMARDs is not recommended. Researchers have shown that serious infections develop in patients taking both of these agents without an important enhancement in efficacy. Common adverse reactions include headache, hypertension, nausea, pharyngitis and upper respiratory infection.13-18
Rituximab (Rituxan, Genentech) received FDA approval in February. It is a chimeric IgG monoclonal antibody that binds to and destroys B-cells but not stem or plasma cells. The key feature of this agent is that it destroys mature B-cells but not the young ones. Rituximab is indicated for patients who have not improved with TNF antagonist therapy.

Controlled clinical trials have provided evidence that rituximab has a favorable risk-benefit ratio in patients with RA in whom TNF-a therapy was inadequate. Studies have also shown clinically meaningful improvements in patient reported outcomes. Researchers have also shown improvements in ACR20, 50 and 70 responses as well as improved DAS28.

At this time, no data is available on the effects of rituximab when it comes to slowing radiographic progression of the disease. Researchers have reported some adverse events related to infusion reactions.18-21

What About Other Biologic Therapies In The Research Pipeline?
In addition to the new agents already approved for those patients with an inadequate response to TNF antagonists, researchers are currently investigating other agents for possible use. Although the future role of any of these new approaches is speculative at present, some interesting targets include new cytokines (IL-6, IL-15, IL-18), osteoclast activity regulators, intracellular metabolic modulators (MAPK, NF-kB) and information from gene expression profiling.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine. There are elevated levels in both serum and synovial fluids among patients with RA, and researchers have also reported a correlation between serum levels and the degree of radiographic damage.

Tocilizumab (Actemra) is a humanized monoclonal antibody directed against the IL-6 receptor. Preliminary clinical trials involving those with refractory RA presented evidence that tocilizumab was successful in decreasing disease activity compared to the placebo group, and was more effective when researchers used it in combination with methotrexate.22 Studies involving the safety of this intervention are currently being conducted.

IL-15 is a potent T-cell attractant that is elevated in synovial fluid and synovial membranes in patients with RA. Some preliminary studies suggest this cytokine is involved in the perpetuation of RA synovitis.23
Researchers have shown that IL-18 promotes collagen-induced arthritis in mice. It promotes articular TH 1 responses and acts directly on macrophages to induce proinflamatory cytokine production.23
Researchers have also demonstrated that receptor activator of NF-kB ligand (RANKL) and osteoprotegerin are critical regulators of osteoclast generation and activity. Some authors have found that RANKL protein is confined to sites of osteoclast-mediated erosions at the pannus-bone interface and may play an important role in the pathogenesis of arthritis-induced joint destruction.24

Controlled clinical trials have shown that rituximab (Rituxan) has a favorable risk-benefit ratio in patients with RA in whom TNF-a therapy was inadequate.

Kinase proteins appear to play an important regulatory role in inflammatory diseases. P38 MAP kinase is a protein that turns on the production of inflammatory cytokines. Researchers have shown that inhibitors of p38 MAP kinase decrease inflammation in preclinical models. Blocking intracellular phosphorilation can inhibit adjuvant arthritis in animal models. Currently, investigators are conducting a phase II, multicenter clinical trial with an oral p38 MAP kinase to determine if it reduces inflammation in patients with RA.25,26
The DNA binding capacity of the nuclear transcription factors AP-1 and NF-kB are markedly increased in both collagen-induced arthritis in mice and in patients with RA. Studies have begun in animals to determine the feasibility of inhibiting these factors in RA.

Using gene expression profiling, it is now possible to obtain dynamic information regarding relative gene expression. One can use this information to monitor disease progress as well as therapeutic responses. Armed with this information, clinicians may eventually be able to identify RA patients who are destined to have progressive disease and/or be at increased risk for developing therapeutic toxicity. For example, researchers have shown that, among patients with early RA, there is a correlation between susceptibility to infection and type (upper respiratory infection or urinary tract infection) dependent upon single nucleotide polymorphisms (SNPs) in TNF, LFA and Fcy receptor genes.27

Translating The Research Into Clinical Practice
As noted above, recent clinical studies have provided evidence that joint destruction occurs early in the disease and aggressive therapy with DMARDs (both classic as well as biologics) can lead to retarded progression of joint destruction, improved quality of life, decreased clinical symptoms and delayed disability. Based on these findings, the message is clear. We must diagnose RA early and treat it early in the disease process with DMARDs.28-32

Primary care clinicians are most commonly the first to see patients with joint pain and consequently are viewed by many to represent the “front lines” of RA care. With the recent advances in our understanding of the importance of early diagnosis and treatment, primary care health professionals are now in a position to apply this new scientific knowledge into daily practice. None of this will be possible unless all health professionals get involved. By working with rheumatologists in proactively assessing, diagnosing and treating at-risk patients, primary care health professionals are in a position to make a significant impact on RA outcomes.

However, it will require more than individuals and health professionals acting alone. It will also require a state and/or national plan utilizing a coordinated public health approach involving shared leadership with multiple stakeholders (e.g., public, private, non-profit, academic) who are willing to cooperate to deliver the appropriate patient-centered care.