Given the debilitating effects of rheumatoid arthritis and recent changes in the evolution of RA treatment, these authors review the literature and discuss the potential impact of combination therapy for this disease.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that primarily targets synovial tissues and results in extensive destruction of cartilage and bone. The disease occurs worldwide and has a prevalence of 0.03 to 1.5 percent in the United States.1 Women are affected three times more often than men and tend to have an earlier onset of the disease, typically during childbearing age.2

Early in the disease, pain and fatigue from systemic inflammation are the leading reasons for missed work and disability. However, as the disease progresses, joint destruction becomes the dominant cause of disability. Early diagnosis and treatment of RA are critical to limit inflammation and prevent joint damage. Delayed treatment often leads to substantial disability, functional decline, economic loss and work impairment.
Rheumatoid arthritis is also associated with an increased risk of coronary heart disease, infections, lymphoma and reduced life expectancy.3 While there is no cure for RA, the goal of treatment is remission induction and maintenance of remission leading to an improved quality of life.

In the previous few decades, medical management of RA was one of a pyramid or sequential approach. The disease was commonly managed by the use of nonsteroidal antiinflammatory drugs (NSAIDs). Clinicians often avoided the use of drugs now known as disease-modifying antirheumatic agents (DMARDs) until joint damage was evident.



However, as we have learned more about the pathophysiology of the disease and with the introduction of new, more effective medications, the pyramid approach is being replaced by a more aggressive therapeutic approach. The treatment of RA still utilizes NSAIDs and analgesics to relieve pain and stiffness. However, it has been recognized that these agents have limited effects on slowing the progression of destructive RA. In contrast, DMARDs improve symptoms and retard erosive damage. In cases of clearly defined RA, clinicians now initiate these agents as soon as possible and often use them in combination to provide maximum benefit.

What About The Pathophysiology Of RA?
The ultimate cause of RA remains unknown but immunologic, genetic and environmental factors have been implicated. Rheumatoid arthritis results, at least in part, from a dysregulated immune system that leads to uncontrolled and persistent inflammation within the lining of joints. Immune cells including T cells, B cells, dendritic cells and macrophages have all been linked to RA. Furthermore, when these immunocytes are activated, many of them release a variety of inflammatory mediators (cytokines), including tumor necrosis factor-a (TNF-a).

TNF-a is a central component in the cascade of inflammatory cytokines and is involved in further recruitment of inflammatory cells into the joint lining (pannus) and joint space.4 A combination of activated proteases and recruitment and activation of neutrophils lead to the breakdown of cartilage and bone. Current treatments are aimed at disrupting cellular components of the inflammatory response as well as the cytokines which propagate this complex inflammatory network.

How The Treatment Approach To RA Has Changed In Recent Years
The currently accepted management for RA begins with establishing the diagnosis of RA early and documenting disease activity and damage. Then the goal is initiating an effective therapy as early as possible.

In practice, it is also very critical to educate the patient about the natural history of RA and the need for complicated medication regimens and frequent monitoring. In most cases, the goal is to introduce DMARDs within three months of the diagnosis.



Clinicians often use corticosteroids early in the management of RA in combination with DMARDs and analgesics. Corticosteroids, even at low doses, are often very effective at providing short-term relief from symptoms of RA and can bridge the gap until DMARDs have established pharmacologic efficacy. Some recent studies suggest that prednisone at 5 to 10 mg daily may initially slow the rate of radiographic progression.5-7 However, retrospective studies suggest excess adverse events may develop even after as few as three months.8 Therefore, the potential use of corticosteroids in the early management of RA requires careful risk/benefit discussions with patients.

What You Should Know About Methotrexate
Disease-modifying antirheumatic drugs include conventional DMARDs and biologic DMARDs. Conventional DMARDs include methotrexate (Mtx), sulfasalazine (SSZ), hydroxychloroquine (HCQ), leflunomide, cyclosporine, azathioprine and minocycline. Current biologic DMARDs include infliximab (Remicade, Centocor), etanercept (Enbrel, Amgen/Wyeth), adalimumab (Humira, Abbott), abatacept (Orenica, Bristol-Myers Squibb) and rituximab (Rituxan, Genentech) while many more are in development.

Due to its long-term effectiveness and demonstrated ability to slow disease progression, methotrexate (Rheumatrex, Stada Pharmaceuticals) is the most commonly prescribed DMARD. Methotrexate acts within weeks to months and its clinical effects are dose-dependent, which allows for dose titration to control disease activity. Typically, clinicians start the medication at a dose of 7.5 to 15 mg weekly. Then one escalates the dose to a maximum tolerated dose of 20 to 25 mg. One may improve both tolerability and bioavailability with parenteral (subcutaneous/intramuscular) administration.

Patients should also receive folate supplementation (1 to 5 mg daily) to reduce the toxicity of the drug. The most common side effects include oral ulcers, nausea, diarrhea, altered liver function tests (LFTs), alopecia and idiosyncratic pulmonary reactions. According to the American College of Rheumatology (ACR) guidelines, clinicians should monitor patients every one to two months with lab work, including CBC, LFTs and serum creatinine.9

Despite being an effective DMARD, methotrexate alone often does not eliminate progressive bone destruction and synovial proliferation. Therefore, using this medication as a monotherapy does not always induce remission.

In several clinical trials, initial combination therapy including methotrexate increased the number of clinical remissions and the durability of such responses to therapy.

A Guide To Other Commonly Used DMARDs
Aside from methotrexate, the most commonly used DMARDs include leflunomide, hydroxychloroquine and sulfasalazine.

Leflunomide is used at a dose of 10 to 20 mg daily. Side effects mainly include nausea and diarrhea. Toxicities include altered LFTs, cytopenias and teratogenicity. One should monitor CBCs and LFTs every one to two months and clinicians should exercise caution with this drug when treating women of childbearing potential as the drug has a long half life.

Hydroxychloroquine is commonly dosed at 200 mg twice a day (maximum 6.5 mg/kg). This is generally considered the safest DMARD although it also has the least evidence to support radiographic benefit. No lab monitoring is needed. Side effects are minimal and toxicities mainly include retinal toxicity. Accordingly, these patients should have annual eye exams.

Here is an outline of the management of rheumatoid arthritis. Boxes with heavy borders represent major decision points in management. A suboptimum response to methotrexate (MTX) is defined as intolerance, a lack of satisfactory efficacy with a dosage of up to 25 mg/week or a contraindication to the drug. DMARD = disease-modifying antirheumatic drug; NSAID = nonsteroidal antiinflammatory drug; mono Rx = monotherapy; combination Rx = combination therapy.

When it comes to sulfasalazine, clinicians generally prescribe this as two or three divided doses daily up to 2 to 3 grams a day. Side effects include nausea and diarrhea. One can limit these effects by emphasizing a slow escalation of dosing over several weeks. Toxicities include suppression of the bone marrow and liver toxicity requiring routine laboratory monitoring.

Combination DMARDs have been shown to be more effective than monotherapy in various trials. “Triple therapy” with methotrexate, sulfasalazine and hydroxychroloquine, and “the COBRA regimen” of sulfasalazine, methotrexate and high-dose oral steroids have both proven to be better than monotherapy.10-14

When Should You Add Biologic Agents?
Recognizing that patient preferences are variable and that clinician practice styles differ, it is generally suggested that if RA disease activity significantly persists beyond three months of maximal therapy, it is time to add biologic DMARDs.

Views also differ as to what constitutes active RA or an inadequate response to current therapy.15 Many rheumatologists rely on clinical gestalt alone rather than objective measures of RA disease activity. However, several studies have demonstrated the benefit of using regularly performed disease assessment guidelines to direct changes in therapy.16-17 In concert with the larger quality initiative in healthcare, documentation of objective measures of RA activity will likely become part of the quality initiative in rheumatology in the near future.

Understanding The Impact Of TNF-a Inhibitors
The revolution in immune-based therapies began with the introduction of etanercept in 1998. Tumor necrosis factor acts as a proinflammatory cytokine in normal immunity. However, an overly robust tumor necrosis factor-dependent inflammatory response fuels the synovial pannus of RA patients.4 A blockade of TNF inhibits the inflammatory disease process and halts disease progression in RA.

Currently available TNF-a inhibitors include infliximab, adalimumab and etanercept. Infliximab and adalimumab are both monoclonal anti-TNF antibodies. Etanercept is a fusion protein consisting of two p75 TNF receptors coupled to the Fc portion of a standard human IgG1 immunoglobulin molecule. As the name TNF inhibitor implies, all of these agents bind to TNF molecules and prevent interaction with its receptors on target cell surfaces, thus limiting propagation of the autoimmune inflammatory response. Clinicians dose etanercept at 50 mg sc weekly, adalimumab at 40 mg sc once every one to two weeks, and administer infliximab via infusion at 3-10 mg/kg every four to eight weeks.

The ultimate goal in treating RA is to achieve remission, a state of little or no disease activity resulting in no progression of structural damage. The available TNF-a inhibitors have clearly revolutionized the treatment of RA, getting more patients than ever at or near the goal of clinical remission. These drugs have been evaluated in a series of randomized controlled trials that have enrolled thousands of patients with RA over the past 10 years. The majority of patients who receive TNF inhibitors get a significant benefit in both signs and symptoms of RA as well as inhibition of structural damage. Furthermore, in all studies to date, the combination of TNF inhibitors with methotrexate (or comparable DMARDs) outperformed either DMARD or TNF inhibitors alone.

Assessing The Impact Of Combination Therapy
Two recent studies have addressed the issue of coupling combination therapy with close monitoring of disease activity.

The TICORA study was a single-blind, controlled trial involving 183 patients randomized to intensive management of RA versus routine care.16 Intensive outpatient management of RA substantially improved disease activity, radiographic progression and quality of life at no additional cost.

The BeST study was a multicenter, randomized clinical trail that enrolled 508 patients with early active RA and divided them into four groups.17

* Group 1 was treated with one drug at a time (sequential therapy). Researchers started with methotrexate and switched to other DMARDs in succession for inadequate therapeutic responses.
* Group 2 began with methotrexate and then the study authors added other DMARDs to current therapy (step up therapy).
* Group 3 started on methotrexate, sulfasalazine and high-dose prednisone (DMARD combination therapy).
* Group 4 patients began treatment with the combination of methotrexate and infliximab (DMARD with biologic combination therapy).

This study demonstrated that patients who were started on initial combination therapy (groups 3 and 4) showed greater functional improvement and less radiographic damage than groups 1 and 2 after the first year of follow up.17

What You Should Know About Adverse Effects Of TNF Inhibitors
Common minor adverse events include injection site reactions with etanercept and adalimumab, and infusion reactions with infliximab. Rare adverse events include optic neuritis, multiple sclerosis-like sequelae, aplastic anemia, interstitial lung disease, lupus like syndrome and hepatotoxicity. Overall, patients taking TNF inhibitors are at an increased risk for infections, particularly of the skin and respiratory tract.

Due to the risk of reactivation of tuberculosis (TB) associated with TNF inhibitors, clinicians must screen patients for TB with PPD skin testing (+/- CXR) or the more recently developed QuantiFERON TB gold test. If the TB screening test is positive, then clinicians may treat these for latent tuberculosis with INH prior to or concurrently with the biologic.18



Additionally, one should avoid the use of TNF inhibitors in the presence of chronic infections. Live vaccination is contraindicated in patients receiving TNF inhibitors as well as those on other DMARDs such as methotrexate.19

To date, there are no specific monitoring requirements for the use of anti-TNFs. However, patients should regularly undergo assessment for clinical evidence of serious side effects such as infection and clinicians should warn these patients to contact a physician in the event of fever or symptoms of infection. Due to reports of cytopenias and liver toxicity, it may be prudent to check periodic blood counts and liver function tests as well. Clinicians should stop treatment with these agents if there is no evidence of efficacy within three to six months. Treatment should be withheld during infections and prior to surgery. Limited data is available on the safety of TNF inhibitors in patients who are pregnant.

The risk of cancers associated with anti-TNF agents is controversial. Researchers have reported solid malignancies and an increased risk of lymphomas with all TNF inhibitors.20 However, there is also a preexisting association of malignancies in patients with active RA. Currently, it is probably wise to avoid these agents in patients who have a history of malignancy and one should also warn patients that the cancer risk with anti-TNF therapy is unknown at this time.

Clinicians should also exercise caution when it comes to using TNF inhibitors in patients with mild heart failure.21 These agents are contraindicated in patients with class 3 and 4 heart failure. However, there is currently no evidence that they increase the risk of new onset cardiac failure in patients with RA.

Which Anti-TNF Agent Should You Use?
Currently, there are no published clinical trials that compare one TNF agent to another. No single agent has demonstrated clear superiority. Accordingly, the choice of agent often depends on other factors including patient convenience, access to treatment and clinician preference. TNF inhibitors have been primarily studied in combination with methotrexate. There is limited data regarding their use with other conventional DMARDs. However, in patients intolerant to methotrexate, the use of the aforementioned DMARDs seems logical.

When Patients Have An Inadequate Response To TNF Inhibitors
In patients who have refractory disease to a combination of methotrexate and a biologic, or intolerance to anti-TNF biologics, new options have become available in 2006. These include the costimulation inhibitor abatacept and the anti-CD20 antibody rituximab.

Abatacept modulates the immune response by binding to CD80/86 on antigen presenting cells (such as dendritic cells, macrophages or B cells). Accordingly, this agent prevents costimulatory binding of CD28 and prevents full T cell activation. In a study of patients previously treated with anti-TNFs, researchers reported a significant improvement in patients treated with abatacept.22



Rituximab binds to the cell surface marker CD20 on peripheral B cells, leading to the rapid elimination of B cells from the circulation. The prevailing thinking on B cells is they contribute to the pathophysiology of RA through antibody production, cytokine production and direct antigen presentation to T cells. Three trials have demonstrated the efficacy of rituximab in moderate to severe RA.23-25 Rituximab is currently approved for patients who have inadequate responses to TNF antagonists and are receiving concomitant methotrexate.

Other Treatment Considerations
When managing RA, one may also consider other treatment modalities that may provide significant enhancement in the patient’s quality of life. For those with significant damage to the joint, surgical intervention may prove useful.

Additionally, clinicians should screen all patients for osteoporosis and initiate treatment with calcium, vitamin D and bisphosphonates as needed. Finally, patients with RA are at high risk for coronary artery disease and need appropriate management of lipids and other coronary artery disease risk factors.

In Conclusion
The most important aim of RA therapy is reduction and control of inflammation, and prevention of joint destruction. It is now proven that combination therapy with DMARDs is well tolerated, achieves better symptom control and prevents radiographic damage. Clinicians should tailor the choice of therapy to individual patients, keeping in mind patient-related factors such as acceptability of the drug regimen, affordability and access to health care.

The authors would like to thank Dr. Daniel Stechschulte for critical review of this manuscript and Dr. Herbert Lindsley for providing photographs of early RA.