Keeping Up With Changes in Rheumatoid Arthritis Management

Keeping Up With Changes in Rheumatoid Arthritis Management


Overview of Rheumatoid Arthritis (RA)

RA is, by far, the most common systemic inflammatory condition seen in medical practice and pharmacists, in a variety of practice settings, will commonly interface with patients with this chronic arthritide. RA is characterized by symmetrical bilateral joint involvement and articular destruction with a host of potential extraarticular manifestations including rheumatoid nodules, vasculitis, ophthalmologic inflammation (episcleritis), and neurologic and/or cardiopulmonary disease.1 In addition, lymphadenopathy, splenomegaly, neutropenia, thrombocytopenia, or renal involvement can occur.1 The opportunity for pharmacists to provide education regarding nonpharmacological and pharmacological therapies for patients with RA is immense and presents an excellent chance to substantially impact the care of patients with this chronic and, as yet, incurable condition.

Etiology

Pannus, the inflamed, proliferative joint synovium characteristic of RA eventually invades and destroys the soft and bony tissues of articular joints. (See Figure 1) Unfortunately, RA is associated with the malfunction of both the humoral and cell-mediated functions of the immune system, both of which contribute to the pathophysiology of RA. It is well realized that rheumatoid factor (RF) and antibodies derived from B lymphocytes (plasma cells) are commonly present in patients with RA, with seropositive patients tending to experience more severe and more aggressive disease.2 In patients with RA, the complement (C) system exacerbates and potentiates the dysfunctional immune response and encourages chemotaxis, phagocytosis, and lymphokine release. Tumor necrosis factor (TNF) and interleukin (IL)-1 and IL-6 are also involved in the proinflammatory process. In addition T and B lymphocytes and macrophages all contribute to produce a variety of cytotoxic substances that are detrimental to joints and associated soft tissues.2 Histamine release and prostaglandin production also contribute to the inflammatory process by increasing the permeability of blood vessels.2 Together these substances contribute to edema, warmth, and the erythema and pain associated with RA. The end result of these aforementioned processes lead to a variety of joint pathology, which may include loss of joint space as a result of cartilage degradation, bony fusion known as ankylosis, laxity of tendon structures, leading to subluxation and joint instability, and/or tendon contracture, contributing to joint deformity.1

Epidemiology

RA is estimated to affect approximately 1% to 2% of the United States population, affecting 3 times as many women as men (between the ages of 15 and 45 years, RA affects 6 times as many women as men) and can occur at any age, with an increasing prevalence up to the 7th decade of life. As yet unproven, genetic predisposition may be a factor in disease development, as well as exposure to a yet-to-be identified environmental substance may trigger disease expression.1

An underappreciated aspect of RA is that roughly 50% of patients leave the work force within 10 years of diagnosis and the costs incurred by patients rival those of coronary artery disease or stroke.3

Risk Factors

Specific risk factors for RA are elusive and the precise cause is unknown. Unknown environmental contributors, for example viral infections, are thought to play a role.4 In addition, a birth weight greater than 4.54 kg elevates one’s risk of developing RA.4 Major histocompatibility complex molecules located on T lymphocytes appear to play an important role in disease predisposition. In fact, patients with human lymphocyte antigen (HLA) DR4 are 3.5 times more likely to develop RA than patients with other HLA antigens.4 Interestingly enough, high coffee consumption, particularly decaffeinated coffee, has been proposed to contribute to RA risk, while high vitamin D intake, tea consumption, and oral contraceptive use have been associated with decreased risk.5,6,7

Diagnosis: Signs and Symptoms of Early Diagnosis

Common clinical presentation is of a patient with self-described joint discomfort and stiffness more than 6 weeks in duration, who may also complain of fatigue, weakness, low-grade fever, and lack or loss of appetite. Wrists, hands, ankles, and feet are often initially affected with joint pain, often described as joint tenderness, which is also accompanied by warmth and swelling. Bilateral symmetrical joint involvement is common and rheumatoid nodules may be evident in early disease. Rheumatoid nodules occur in as many as 20% to 30% of patients with RA and most commonly occur on extensor surfaces of the elbows, forearms, and hands; nodules can also occur in the lungs and pleura and, in general, are asymptomatic and do not require treatment. Virtually any articular joint can be affected and, with longer disease duration, shoulders, elbows, knees, hips, and even the jaw or neck can become diseased.8 Joint deformity is not always evident initially, however the patient may report muscle pain and pronounced afternoon fatigue.

In addition to the common and early signs and symptoms previously discussed, laboratory assessment of patients with RA include positive rheumatoid factor (present in 60% to 70% of patients) and the presence of anticyclic citrullinated peptide (anti-CCP) antibodies, along with elevations in the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), both of which are nonspecific markers of inflammation.1 Furthermore, normocytic-normochromic anemia and thrombocytosis may be present.1

Differential diagnosis

The differential diagnosis of RA includes a host of conditions, and patients should always be directed to a rheumatologist for an extensive workup and evaluation. The differential diagnosis includes, but is not limited to, connective tissue disease, sarcoidosis, fibromyalgia, psoriatic arthritis, osteoarthritis, crystal-induced arthritis, systemic lupus erythematosus (SLE), and ankylosing spondylitis.9 There are a multitude of conditions that may present with a positive RF.9 In addition to RA, patients afflicted with Sjögrens syndrome, SLE, progressive systemic sclerosis, or polymyositis may be RF positive. A host of infectious diseases, such bacterial endocarditis, syphilis, mononucleosis, and infectious hepatitis and leprosy may be associated with a positive RF.9 Sarcoidosis, aging, cirrhosis of the liver, and chronic active hepatitis may also be associated with a positive RF.

Benefits of Early, Aggressive Therapy

RA may take a variable and oftentimes an unpredictable course; however the majority of patients experience a persistent, albeit sometimes fluctuating, course that is accompanied by a progressive degree of functional impairment brought on by pain and structural joint abnormalities. Degree of eventual disability is often correlated with the number and degree of joints affected, extensive ESR elevations, and high titers of RF, as well as the early evidence of bone erosions and the presence of rheumatoid nodules. Very early in the disease course, however, it is often challenging to predict which patient will progress to severe disability and which patient will stabilize.

The basic principles and goals of treating RA are as follows: 1) to relieve pain; 2) to control and reduce inflammation; 3) to protect against joint destruction; 4) to control systemic involvement; and, 5) to maintain or improve function and quality of life. The general approach to treating a newly diagnosed patient has undergone a dramatic transformation during the past few years. Previously it was recommended to treat with a nonsteroidal anti-inflammatory drug (NSAID) first and then progress to disease-modifying agents later in the disease course. Today, a disease-modifying antirheumatic drug (DMARD) is recommended as first-line therapy, while NSAIDs and/or corticosteroids can be coadministered but are no longer considered appropriate as initial monotherapy. This is because it is now recognized that a substantial amount of the overall joint damage occurs early in the disease rather than later, as originally thought. While corticosteroids and NSAIDs play a crucial role in providing analgesia and treating inflammation, they do not prevent joint damage or slow disease progression and also have potentially debilitating long-term side effects. In one study by Fuchs and colleagues, 80% of RA patients had joint space narrowing of the hands and wrists within 2 years, while 66% had boney erosions during that same time.10 Early, aggressive treatment has now become the gold standard and is advocated to quell ongoing inflammation and prevent, or at least delay, joint injury.11 Therefore, every patient with established disease should be treated with a DMARD as early as possible.

Another treatment approach recently adopted by some rheumatologists is to initiate treatment with combination DMARD therapy.12,13 Patients started on 2 or 3 DMARDs at the time of diagnosis are more likely to attain remission and maintain optimal functional and clinical outcomes, when compared with patients initially treated with one DMARD.

Early aggressive therapy varies by definition, but generally refers to the treatment of patients with methotrexate (MTX) or a biologic DMARD agent, also known as biologic response modifiers (BRMs), early in the disease course. Certainly as DMARDs or BRMs are introduced, coadministration with an NSAID may be appropriate and, in some instances, the concurrent use of a corticosteroid is advantageous initially, however long-term use of corticosteroids may have significant side effects.

Factors associated with poor outcomes may be useful for identifying early RA patients who have a greater likelihood of disease progression. These include a positive RF test, the presence of anti-CCP antibodies, early radiographic evidence of boney erosive disease, impaired functional status, and persistently active synovitis with high levels of disease activity.14 These patients may be considered appropriate candidates for the use of biologic DMARDs/BRMs at the time of diagnosis.

A 2007 analysis of pooled data from several early RA trials using combination therapy (traditional DMARDs plus BRMs) revealed that the level of disease activity at baseline and during the first 3 months correlated meaningfully with the level of disease activity at 1 year.15 The authors concluded that early RA patients who have not achieved lowered disease activity within the initial few months of standard DMARD therapy may be candidates for BRMs.

All patients receiving DMARDs should be monitored at regular intervals to evaluate the efficacy of treatment, using standard measures of disease advocated by organizations such as the American College of Rheumatology (ACR).16 (See Table 1)

tbl1

Gaps in RA Patient Care

Education: Clinician and Patients

Rheumatologists and pharmacists have much work to do in the area of educating both non-rheumatological medical colleagues and patients regarding the devastating consequences of RA. Undertreatment and misunderstanding of the disease course can have a dramatically negative impact on patients’ lives. Therefore, both clinicians treating RA and patients with this diagnosis need to be persistently and effectively educated. In addition to understanding the rationale for early and aggressive treatment, every clinician and patient should be aware of the critical importance of nonpharmacological modalities that include patient education, physical activity, and appropriate rest, as well as physical, occupational, and dietary therapy; this may include the use of devices to protect joints and their function. Diligent adherence to both nonpharmacological and pharmacological treatments is vital for patients to receive the benefits of each. Pharmacists play a critical role in adherence to all forms and modalities of treatment and should take this responsibility seriously.

Despite the best intentions of medical teams treating and researching RA, gaps in care persist. Although a great number of patients with RA are helped substantially by the available therapies, an estimated 30% of patients with RA, usually those with the most severe forms of the disease, do not demonstrate a response to any treatment. In addition, adverse effects may limit the usefulness of certain agents.17 Ensuring patient adherence is always a difficult challenge, especially with injected therapies and multidrug regimens.17,18

A recent large-scale study investigating the needs of RA patients (Developing Superior Understanding of RA Patients’ Needs [DESIGN]) was conducted to explore the attitudes and behaviors of RA patients and health care providers regarding the disease and its treatment.19 The findings, reported during the 2008 ACR Annual Scientific Meeting, showed that 37% of United States (U.S.)-based patients were dissatisfied or extremely dissatisfied with their level of pain from RA. Only 9% of U.S. patients responded that they were satisfied or extremely satisfied. These findings demonstrate that pain control remains an extensive unmet need in RA disease management efforts, study investigators concluded.

The survey also identified educational gaps associated with RA. For example, the vast majority of physicians (87%) and nurses (90%) surveyed regarded their patients as having a high level of RA knowledge, while only 50% of patients said their knowledge level was high.19

Another RA patient needs survey entitled RAISE (Rheumatoid Arthritis: Insights, Strategies and Expectations), whose results were revealed at the 2009 ACR Annual Scientific Meeting, showed that biologic users reported substantially more good days per month than those not using biologic therapies for RA, but that 22% experienced high levels of pain.20 Among those not using biologic therapies for RA, 62% were not aware of this therapeutic option (despite being eligible) and 88% had never had it recommended by a clinician.20

Current Management Approaches

Review of Classes

There are 3 general broad categories of medications used to treat RA: 1) anti-inflammatory agents, which include NSAIDs and corticosteroids; 2) disease-modifying antirheumatic drugs (DMARDs); and 3) biologic DMARDS, also known as biologic response modifiers (BRMs) or biologics. (See Table 2)

tbl2

Anti-inflammatory Agents

Historically, anti-inflammatory agents for the treatment of RA include NSAIDs and corticosteroids (e.g., prednisone), which were at one time the first-line agents for the treatment of RA. During the past decade, though, it was realized that both NSAIDs and corticosteroids, while effective for treating pain and inflammation, did little to slow the progression of the disease. Therefore, DMARDS have become the recommended first-line choice, with the use of NSAIDs and/or glucocorticoids used concomitantly only to quell pain and inflammation without the benefit of halting or slowing the course of the disease.21

DMARDs

DMARDS are often used as first-line treatment for newly diagnosed disease and include methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine. At one time, in addition to the aforementioned DMARDs, azathioprine, D-penicillamine, gold compounds, minocycline, cyclosporine, and cyclophosphamide were used as second-or third-line treatments, but, because of concerns about questionable efficacy and the more profound risk of toxicity, these DMARDs are less frequently used today.11,16 Currently, it is much more likely that a combination oral therapy with safer agents or the combination of a single oral agent and an injectable BRM would be used in conjunction with common dual therapies, such as methotrexate and etanercept or methotrexate and infliximab. Combination oral therapies, such as methotrexate plus sulfasalazine or methotrexate plus hydroxychloroquine, in particular, are also effective dual oral DMARD therapeutic approaches.22

Methotrexate

Methotrexate is a folate antagonist that suppresses purine biosynthesis, inhibits cytokine production, and stimulates adenosine production, all of which contribute to its anti-inflammatory action. Symptomatic relief is often achieved in the first month of therapy and methotrexate is associated with persistence of use in many patients. In addition to being used orally, methotrexate can be injected intramuscularly or subcutaneously, however the most common route of administration is oral. Monitoring of therapy is reviewed in Table 1. Common side effects of methotrexate include nausea, vomiting, and abdominal distress, all of which are often self-limiting when used at antirheumatic dosages. Paradoxically, rheumatoid nodules can increase in size with methotrexate therapy.23

The one particular aspect of methotrexate therapy that pharmacists must be aware of concerns the addition of folic acid to the regimen of a patient using methotrexate. Folic acid will decrease the likelihood of toxicity and improve the side effect profile and will not, in any way, compromise the response to therapy; so, if a pharmacist is working with an RA patient currently on methotrexate and not using folic acid; the patient’s prescriber should be contacted to determine if concomitant therapy with folic acid was inadvertently overlooked.

Leflunomide

In contrast to methotrexate, which alters purine synthesis, leflunomide is a DMARD that inhibits pyrimidine synthesis, thereby altering lymphocyte activation and decreasing the inflammatory response. See Table 1 for monitoring guidelines. Methotrexate and leflunomide are equally efficacious. An unusual caveat to leflunomide therapy is that pregnancy should be avoided because leflunomide is teratogenic and precautions against pregnancy must be taken, by both men and women, on therapy. Leflunomide undergoes enterohepatic circulation and, therefore, in cases of toxicity or in patients desiring to conceive a child, cholestyramine is required to quickly bring down blood levels; without this strategy it would take months to remove this drug from the body.24

Hydroxychloroquine

Hydroxychloroquine is one of the safest oral DMARDs for the treatment of RA, being devoid of myelosuppression and renal or hepatic toxicity and with ophthalmologic toxicity approaching zero; however, routine ophthalmological evaluation is recommended.25 Side effects tend to be mild, with vomiting, nausea, or diarrhea easily lessened by administration with food. One of the drawbacks of hydroxychloroquine is it may take up to 6 months for patients to respond and, in general, if no response is experienced between 6 and 9 months, the drug should be discontinued.

Sulfasalazine

Sulfasalazine is not active until it is cleaved by intestinal bacteria to sulfapyridine and 5-aminosalicylic acid (5-ASA). Therefore sulfasalazine is a prodrug with the active metabolite thought to be sulfapyridine. 26 Antirheumatic response if often seen within 2 months; however, unlike methotrexate, its persistent use is frequently hindered by intolerable side effects which include nausea, vomiting, diarrhea, and anorexia. Monitoring parameters are summarized in Table 1. An important counseling point for pharmacists is to relay to patients using sulfasalazine is that it may turn their skin or body fluids a yellow-orange color, but this is of no clinical consequence. Furthermore, sulfasalazine can bind iron and its absorption can be decreased if antibiotics destroy the patient’s intestinal microflora. Both of the former points are important for pharmacists to communicate to their patients on sulfasalazine therapy.

Newer Options: Biologic DMARDs/BRMs

There are 5 basic categories of biologic DMARDs/BRMs (see Table 2): 1) TNF antagonists; 2) IL-1 receptor antagonists; 3) IL-6 receptor antagonists; 4) costimulation blockers; and 5) anti-CD20 monoclonal antibodies. All of the commercially available biologic DMARDs are genetically developed protein molecules that have various actions on the pathogenesis of RA. One of the distinct advantages of the biologic DMARDs are that they do not require routine laboratory monitoring (see Table 1); however biologic DMARDs generally do increase the likelihood of infection and all therapy must be temporarily suspended if the patient experiences an acute infection. Furthermore, as these agents may increase the risk of tuberculosis, all patients should receive a tuberculin skin test evaluation prior to use.16 Theoretically, TNF inhibitors may pose the risk of malignancies; however, there are no data substantiating or supporting this and continued postmarketing surveillance is necessary.16 Before we review some specifics of each of the various biologic DMARDs, let’s briefly touch on a few general RA treatment updates.

Treatment Updates

Increasing interest has been focused on the use of antibodies and antibody fragments as the basis for new therapies to combat chronic disease.27 An example relevant to RA is the use of agents that downregulate the function of TNF-alpha (TNF-α), a key cytokine involved in the pathogenesis of RA. Anti-TNF-α agents have been shown to minimize and, in some cases, halt the progression of joint destruction. Although anti-TNF-α agents for RA do not increase the risk for serious adverse events at recommended doses, higher doses are associated with an increased risk of serious infections.28 Selection of the appropriate anti-TNF-α agent for an RA patient is a critical, but complex, decision for clinicians. Advances in biotechnology have made it possible to engineer biologic therapies that harness the functional capabilities of many types of proteins, including enzymes, hormones, cytokines, and antibodies.29,30 One method that has proven successful for overcoming the inherent limitations of proteins used as drug therapy is to covalently join the protein with polyethylene glycol (PEG), a nontoxic, nonimmunogenic polymer approved by the FDA for use in foods, cosmetics, and pharmaceuticals.31 Conjugation with PEG (termed PEGylation) modifies the structure and function of the parent protein, resulting in a compound with potentially improved therapeutic capabilities.

In general, biologic DMARDs are reserved for patients who have failed a proper trial of standard DMARD therapy. Often, when a biologic DMARD is introduced, the patient may remain on the oral DMARD methotrexate or, if the standard DMARD is ineffective, the biologic DMARD would be used as sole therapy, when appropriate (some require the coadministration of methotrexate). The decision to add or substitute with a biologic DMARD is based on many factors, including the clinician's comfort level with the therapy, the frequency and/or route of administration, the manual dexterity of the patient, and the final cost to the patient; the patient’s insurance coverage will also factor into the decision of whether to pursue biologic DMARD therapy. The ACR’s most recent guideline statement, about the use of DMARDs to treat RA, recommends using an anti-TNF-α agent plus methotrexate for patients who have experienced a high level of disease activity for 3 months or longer, a poor prognosis, no barriers related to treatment cost, and no insurance restrictions to accessing medical care.16 Pharmacists involved in the management of RA patients should note that, in general, patients prone to serious infections, those with a history of demyelinating disorders, such as multiple sclerosis or optic neuritis, and patients with any degree of heart failure are not viable candidates for biologic DMARD therapy.16

Specific Review of Biologic DMARDs for the treatment of RA
Tumor Necrosis Factor (TNF) Antagonists

There are currently five FDA approved TNF antagonists approved for the treatment of RA and they are etanercept, infliximab, adalimumab, certolizumab, and golimumab.

Etanercept

The first commercially available TNF-α drug was etanercept, which is a recombinant form of the human TNF receptor, and it works by binding soluble TNF, thereby preventing the activation of TNF receptors. Etanercept is injected subcutaneously once or twice weekly, with self-limiting local injection site reactions being the most common side effect. No laboratory monitoring is required and pharmacists should be aware that patients with multiple sclerosis should not receive this drug. Multiple clinical trials of etanercept as monotherapy have demonstrated superior slowed disease progression when compared with methotrexate.32-34

Infliximab

Infliximab is a chimeric IgG1 monoclonal antibody that binds to TNF-α and requires the coadministration of methotrexate to suppress antibody production against the murine-derived portion of the molecule. Roughly 10% of patients develop antibodies against infliximab, which may predispose a patient to infusion reactions or lessen the efficacy of the drug. Infliximab requires intravenous infusion, administered by a qualified health care provider.35 Infusion-related reactions are not uncommon and may include rash, flushing, headache, fever, and chills, as well as tachycardia or dyspnea. Patients experiencing an infusion reaction should temporarily discontinue the infusion, or slow the infusion rate, and administer acetaminophen, corticosteroids, and antihistamines, such as diphenhydramine. Patients with a history of infliximab-related infusion reactions can be successfully pretreated with corticosteroids and antihistamines to lessen the chance of subsequent reactions. Clinical trials involving infliximab plus methotrexate have demonstrated superior efficacy when compared with those investigating methotrexate monotherapy.36,37

Adalimumab

Adalimumab is a recombinant human IgG1 monoclonal antibody that binds to both soluble and bound TNF-α. Patients often experience symptomatic benefit within 1 to 2 weeks after use and adalimumab can be administered in combination with methotrexate or other DMARDs. Adalimumab has shown similar efficacy to other anti-TNF-α therapies, with local skin injection site reactions being the most common side effect.

Certolizumab

In the treatment of RA, the PEGylated anti-TNF-α agent certolizumab has been shown to bind to and neutralize both membrane-bound and soluble human TNF-α in a dose-dependent manner. Certolizumab is subcutaneously injected at weeks 0, 2, and 4 and then every 2 to 4 weeks thereafter. Optimal response is reported after 14 to 16 weeks of therapy; it has proven to be more effective than methotrexate monotherapy.38,39 Most common adverse reactions are headache, nasopharyngitis, and upper respiratory tract infection. As with other TNF-α therapies, and consistent with this class of therapy, most serious adverse reactions involving certolizumab are infectious in nature, including tuberculosis.

Golimumab

Golimumab is a human IgG1, kappa, monocloncal antibody TNF-α blocker therapy that is used in combination with methotrexate. Golimumab is injected monthly and has a similar side effect profile to other anti-TNF therapies.

IL-1 Receptor Antagonists
Anakinra

There is only one IL-1 receptor antagonist on the market and that is anakinra. Anakinra is a recombinant form of the human IL-1 receptor; when it binds IL-1, subsequent cell signaling is inhibited. One of the potential drawbacks of this medication is the necessity to subcutaneously inject anakinra daily. Anakinra can be used with DMARDs, but it should not be used with TNF antagonists because there is an increased risk of infection with that combination and no additional clinical benefit is afforded by adding anakinra to an anti-TNF therapy. Injection site reactions are the most common side effect reported and the precautions regarding the serious risk of infection are similar to those of other anti-TNF therapies. Pharmacists should be aware that, in general, rheumatologists believe that anakinra is less efficacious than currently available anti-TNF therapies and should be reserved for patients failing other biologic DMARDs.40,41

IL-6 Receptor Antagonist
Tocilizumab

Tocilizumab is an IL-6 receptor-inhibiting monoclonal antibody that binds to both soluble and membrane-bound IL-6. Tocilizumab is administered intravenously every 4 weeks and can be used as either monotherapy or in conjunction with a DMARD (methotrexate).42 Most common side effects include upper respiratory tract infection, nasopharyngitis, headache, hypertension, and increased alanine aminotransferase (ALT). Infusion reactions may also occur. Tocilizumab is reserved for RA patients who have had an unsatisfactory response to one or more anti-TNF therapies.42

Costimulation Blocker
Abatacept

Abatacept, the only costimulation blocker on the market, works by binding to CD80/CD86 receptors on antigen-presenting cells, thereby preventing T cell activation. In patients with RA, when T cells are activated they facilitate the inflammatory process and promote cytokine production and T cell proliferation. Abatacept is reserved for patients who have had an unfavorable response to anti-TNF therapies. Abatacept is administered initially as 2 infusions every 2 weeks and, then, as two infusions every 28 days; side effects are mainly related to infusion reactions. Roughly only 50% of the patients receiving abatacept have an acceptable response.43

Anti-CD20 Monoclonal Antibody
Rituximab

Rituximab is a genetically engineered chimeric anti-CD20 monoclonal antibody and is reserved for patients with moderate-to-severe RA who have inadequately responded to conventional DMARDs and other biologic DMARDs.44 Rituximab works by depleting B lymphocytes. Two infusions are given 2 weeks apart, and its prolonged effect on B cells results in a prolonged duration of action. Methylprednisolone, acetaminophen, and antihistamines are commonly given prior to the infusion to reduce the risk and seriousness of infusion-related reactions. Rituximab possesses a black box warning of fatal infusion reactions and severe mucocutaneous reactions. Side effects include labile blood pressure, cough, rash, and pruritus. Rituximab is reserved for patients who have failed anti-TNF therapies.44

Latest Data on Certolizumab in Patients With RA

Reports from the ACR’s 2009 Annual Scientific Meeting included updates from trials investigating the efficacy and safety of certolizumab plus methotrexate for RA. A study by Keystone and colleagues demonstrated that patients who responded positively in the first 6 weeks of treatment to the combination of certolizumab and methotrexate were also more likely to have better outcomes after 1 year (i.e., ACR responder rates, physical function, pain relief) versus those who were not early responders.45 Similarly, data from Westhovens et al showed that early responders also enjoyed improved household productivity compared with those who responded later to certolizumab.46

These studies, along with others presented at the meeting, continue to support the theory that the time to initial response and the level of early response to this anti-TNF-α combination are strong predictors of 1-year therapeutic outcomes. As with other biologic DMARDs and for certolizumab, clinicians making treatment decisions on behalf of their patients with RA, it is important to recognize that the majority of patients who are going to respond will do so within the first 12 weeks of treatment. 47 Clinical improvements in physical function and health-related quality of life were sustained for more than 2 years in patients receiving certolizumab-methotrexate.48

Furthermore, infections were the most commonly reported adverse event; the rate of serious infection was 5.4 per 100 patient-years.49

Strategies for Enhancing Patient Outcomes

Effective, patient-centered and individualized counseling is required for patients with this chronic incurable condition. General counseling highlights include, but are not limited to, the following 4 points: 1) stress the need for routine and constant consultation with a rheumatologist because RA treatment is rapidly advancing; 2) stress the importance of reporting any changes in general health because changes may be a sign of disease progression or medication side effects; 3) stress the importance of regular evaluation and treatment by a physical therapist and occupational therapist, when appropriate; and 4) stress the importance of weight reduction, rest, and the appropriate use of assistive devices.

Tight Control of RA

“Tight control” has been defined as a treatment strategy tailored to the individual patient, whereby a predefined level of low disease activity or remission, within a certain period of time, is designated as a goal to be achieved.50 A number of recent studies have shown significant benefits for the tight control, or intensive outpatient management of RA, in comparison with routine care.51-53 For example, in a Japanese study of 91 patients with RA who were treated using anti-TNF agents for the duration of 1 year, the benefits of tight control included the reduced need for joint surgery.51

Tight control of RA may involve more frequent monitoring of the patient, or it may include monitoring in combination with a protocol for treatment adjustments. Results of a meta-analysis presented at the 2009 ACR/ARHP Annual Scientific Meeting showed that the latter approach (monitoring in combination with a treatment protocol) was “far more effective than usual care,” while tight control involving monitoring was found to be only slightly more effective.54

The BeSt trial, a randomized clinical trial involving 508 recently diagnosed RA patients, compared effectiveness among the following 4 different treatment approaches: sequential monotherapy; step-up combination therapy; initial combination therapy with methotrexate, plus high-dose prednisone; or infliximab in combination with methotrexate. The combination therapies were associated with less radiologic damage after 1 year than the other 2 strategies and with greater functional improvement.55

Switching Therapy

Among people receiving biologic agents, such as anti-TNF-α agents for their RA, many either do not respond to or have a suboptimal response to therapy.56 For those patients with RA who respond well initially, treatment may lose efficacy over time; because various anti-TNF-α agents differ in chemical structure, mechanism, and safety profile, it is reasonable to consider switching from one anti-TNF agent to another as a viable approach for those who fail or are intolerant to the initial treatment.57 In an Italian study of patients switched from one anti-TNF agent to another, the proportion of patients with good and moderate-good response increased from 5.4% before the switch to 27% 3 months after the switch (P <.000001).56

Productivity Outcomes in RA Studies

Reduced productivity and a compromised quality of life are realistic outcomes for those with RA. The Medical Expenditure Panel Survey indicated that people with RA are 53% less likely to be employed and spend 3.6 times the number of days sick in bed compared with matched controls.58-61 Treatment with combination certolizumab and methotrexate was shown in the recent studies RAPID 1 and RAPID 2 (Rheumatoid Arthritis Prevention of Structural Damage) to increase workplace productivity and reduce absenteeism when compared with methotrexate therapy alone. Improvements were seen as early as 4 weeks and were sustained over time, with certolizumab-treated patients reporting 1 day lost per month by week 52, versus 4.5 days per month for methotrexate monotherpy.62 Productivity in the home was also improved in these trials. Demonstrating increased productivity helps support arguments for the cost-effectiveness of biologic agents for the treatment of RA.59

Conclusion

Management of RA has been a rapidly evolving area of clinical practice during the past 2 decades and pharmacists play a critical role in providing current education regarding the ever-changing approach to treating patients with this common systemic inflammatory condition. Patients are being treated far earlier and more aggressively with different agents upon or shortly after diagnosis. Keeping abreast of these pharmacotherapeutic changes, while being aware of individual patient needs and potential gaps in management, remains a challenge for pharmacists involved in managing patients with RA. However, this provides a unique, albeit challenging, opportunity for continuing education activities that describe current knowledge of RA to both patients and medical providers.

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