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    Treatment of rheumatoid arthritis: A review of recommendations and emerging therapy

    Abstract

    Rheumatoid arthritis (RA) is a complex disease, resulting in localized erosion to the joint and its accessory structures. Due to the progressive nature of the disease, extra-articular complications will occur in multiple organ systems. Over the past decade, the management of RA has evolved with disease-modifying antirheumatic agents with biologic activity targeting specific components of the immune system. With advanced therapy, management includes halting further progression of the disease and maintaining quality of life. The American College of Rheumatology has provided updated guidelines regarding the use of biologic therapies as monotherapy or in combination with nonbiologic therapy such as methotrexate. Unmet needs remain, however, for the management of RA due to the complexity of the disease. Innovative agents are needed to create additional strategies and achieve desired goals for its management. (Formulary. 2011;46:532–545.)

    Rheumatoid arthritis (RA) is characterized as a chronic, inflammatory disease in which the immune system destroys synovial joints and accessory structures.1,2 Due to the progressive nature, this autoimmune condition can cause extra-articular complications within several organ systems.3 RA is the most common autoimmune disease, and the second most common form of arthritis compared to osteoarthritis (OA).1,2

    RA affects approximately 1% of adults all over the world.1,2 Individuals are usually diagnosed between the third and fifth decade of life and women are 2 to 3 times more likely to be diagnosed than men.1,2 Therefore, individuals with RA may experience a lower quality of life and amass a large amount of direct and indirect costs due to the management of the disease, hospitalizations, and physician visits.

    The etiology of RA is not fully understood, but environmental and genetic factors have been proposed as potential theories. Genetic predisposition results in the destructive nature of this autoimmune disease.2 The inheritance of certain genes in the major histocompatibility complex can increase the susceptibility of developing RA. For example, an individual with expression of a human leukocyte antigen (HLA) DR-4 antigen will be 3.5 times more likely to develop RA compared to someone with other HLA-DR antigens.2 Other potential risk factors include female gender, use of oral contraceptives, tobacco use, and infectious agents.2

    PATHOPHYSIOLOGY

    Synovial joints, such as the knee, have the most flexibility due to unity of bones by connective tissue of an articular capsule and accessory ligaments. In RA, the immune response will be activated in an early stage of life. This immune response could be triggered by genetic and environmental factors. Once the immune system is unbalanced, subclinical inflammation will occur due to activation of T cells from an antigen-presenting cell. Once T cells are proliferated, a cascade of events occurs in the immune system: activation of B cells and macrophages, as well as other proinflammatory mediators such as tumor necrosis factor (TNF) and interleukin (IL). As the immune system remains unchecked, symptoms associated with RA will occur and the criteria for the disease will be fulfilled. Once the diagnosis is confirmed, the pathologic inflammatory response can continue, resulting in joint destruction and extra-articular complications. Within a synovial joint, bone and cartilage erosion will occur, causing a swollen joint capsule and inflamed joint synovium. The extra-articular complications can occur over time and include infections, lymphomas, cardiovascular disease, and osteoporosis.1-3

    CLINICAL PRESENTATION


    ILLUSTRATION BY CHRISTY KRAMES, MA, CMI
    RA can occur at any age, but in men onset before age 45 years is uncommon.1 The disease can develop rapidly within weeks to months.3 Commonly affected areas include the hands, wrists, elbows, knee, metatarsophalangeal joint, shoulder, and cervical spine. The area of joint involvement is symmetric and results in pain, morning stiffness lasting more than 1 hour, gelling (or locking with inactivity), tenderness, warmth, redness, and inflammation. Due to the autoimmune nature of the disease, constitutional symptoms will occur such as low-grade fever and malaise. As RA progresses, there can be extra-articular involvement leading to complications, such as vasculitis and pulmonary and cardiac issues. 3

    DIAGNOSIS


    Table 1: Comparison between 1987 criteria and 2010 criteria for rheumatoid arthritis
    In 1987, the American College of Rheumatology (ACR) developed criteria for the classification of this disease.4 Development of newer, more aggressive options, however, has made the ACR classification outdated because the criteria are not sensitive enough to identify early RA. Therefore ACR and the European League Against Rheumatism (EULAR) collaborated to develop new classification criteria for RA in 2010.5 Table 1 compares the obsolete and new classification criteria for the disease.4,5 The new classification criteria are simple to follow for practitioners such as primary care providers to determine an appropriate referral to a rheumatologist. For rheumatologists, the criteria will allow earlier initiation of more aggressive treatment to prevent progression and disability of the disease. Before the new classification criteria can be implemented, 2 requirements must be met to confirm the diagnosis of RA: evidence of clinical synovitis in at least 1 joint (excluding common joints seen in OA), and ruling out systemic lupus erythematosus, gout, and psoriatric arthritis.5 It will take some time, however, for the new criteria to be used by practitioners and implemented in clinical trials.

    MANAGEMENT

    ACR and EULAR have specific treatment guidelines for RA.6-8 Once a diagnosis is made, the combination of nonpharmacologic and pharmacologic therapy should be initiated. Initially, education is always warranted regarding the disease and its progressive nature. Depending on the patient's level of disability, physical and/or occupational therapy should be considered to improve quality of life. Overall, pharmacologic therapy is the mainstay of treatment for RA and can be divided into symptomatic therapy and disease-modifying antirheumatic drugs (DMARDs). Even though the treatment has emerged with innovative, more-specific agents, there is no cure for RA. Aggressive treatment is used to prevent further progression of the disease and help maintain the patient's quality of life.

    TREATMENT OF RA

    In 2008, ACR developed new recommendations from the 2002 guidelines on the treatment of RA.6,7 In addition, EULAR published updated guidelines in 2010, which are similar to the updates by ACR.8 The purpose of the new recommendations was to provide additional guidance from clinical evidence and input of an expert panel. Overall, the guidelines are similar in their recommendations. Treatment with a DMARD should begin as soon as the diagnosis of RA is confirmed. Therapy can be intensified every 3 to 6 months with nonbiologic and/or biologic DMARDs, with methotrexate as part of the treatment regimen unless contraindicated or not tolerated.


    Table 2: Summary of recommendations from the ACR for DMARDs without biologic activity*
    Several key recommendations are included in the updated treatment guidelines. First, methotrexate or leflunomide is recommended for most patients with RA. Both agents have documented improvement in objective assessment of the disease and reduction in radiographic progression. Table 2 summarizes the recommendations for DMARDs without biologic activity from the ACR.7 Combination therapy of a TNF antagonist and methotrexate can be used for patients with newly diagnosed or early RA. If a patient fails a particular TNF antagonist with or without methotrexate, another DMARD with biologic activity can be initiated as long as the patient does not have any contraindications. Failure includes continuation or no improvement in symptoms within 3 to 6 months of pharmacologic therapy or development of poor prognosis. The alternative DMARDs with biologic activity include another TNF antagonist, abatacept, or rituximab with cost, comorbidities, and drug-related risks as the deciding factors.7 Prior to initiation of any DMARD with biologic activity, all patients should be evaluated for active infections (including bacterial), herpes zoster infection, hepatitis B and C, and active or latent tuberculosis. The last recommendation was adding a contraindication of TNF antagonists among patients with heart failure, lymphoma, or multiple sclerosis due to ongoing evidence of a causal relationship. The choice of any DMARD with biologic activity will be based on the severity of the disease, previous response with an agent, and cost.6–8 For the treatment of RA, questions remain regarding the best treatment choice for a majority of patients. Comparative efficacy studies among DMARDs with biologic activity are lacking, as it is difficult to obtain the same patient population and predict the same patient response within a clinical trial. For RA, clinical trials are typically short in study duration; therefore, long-term evidence is limited regarding safety until postmarketing information becomes available.

    Due to the progressive nature of the disease, there can be extra-articular complications for patients with RA. One of the major complications can be cardiovascular mortality or morbidity.9,10 In 2010, EULAR published 10 key recommendations regarding cardiovascular risk screening and management for patients with RA, as well as other inflammatory conditions (ie, ankylosing spondylitis and psoriatic arthritis).9 In general, the recommendations recognize early identification of cardiovascular risk factors due to the increased prevalence in the general population and inflammatory properties of the disease. Adequate risk management and ongoing monitoring is recommended to lower the cardiovascular risk of a patient with RA. For example, it is recommended that all patients with RA should undergo an annual cardiovascular risk assessment using a risk-score model. EULAR recommends the use of national guidelines for determining the appropriate management of a patient's hypertension or yperlipidemia, such as statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. For the treatment of RA, cyclooxygenase (COX-2) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) should be prescribed cautiously for a patient with or without documented cardiovascular disease, weighing the risks and benefits. The lowest possible dose of an oral corticosteroid should be prescribed due to the long-term safety profile (ie, hypertension, yperlipidemia, atherosclerosis). Lastly, smoking cessation should be encouraged among all patients with RA who actively smoke.9

    NSAIDs. NSAIDs have been used in the management of RA for several decades. NSAIDs inhibit COX to prevent further formation of prostaglandins and other related inflammatory mediators. Based on its mechanism of action, NSAIDs are useful adjuvant therapy for the symptomatic management of RA, as this class of medications can reduce joint swelling, tenderness, and pain.6,11,12 All NSAIDs pose anti-inflammatory properties and, when prescribed at high doses, are equally effective. As a class, the main disadvantage of NSAIDs includes the safety profile (ie, gastrointestinal [GI], nephrotoxicity, and cardiovascular). In addition, it is difficult to predict an individual's response with a particular NSAID. Compared to more-specific agents (ie, COX-2 inhibitor), there is no superior evidence between these therapeutic classifications of medications.6,11 Therefore, celecoxib is the only COX-2 inhibitor that can be an alternative agent for an individual prone to GI bleeding or ulcers.

    Corticosteroids. Corticosteroids possess anti-inflammatory and immunosuppressive properties through an unknown specific mechanism. However, it is suspected that these agents have inhibitory properties on the generation and migration of immune system mediators. Similar to NSAIDs, corticosteroids are commonly used for symptomatic management.6,11 The advantage of corticosteroids is the available oral and intra-articular formulations for the treatment of RA. Therefore, a patient can receive systemic or localized corticosteroid treatment based on clinical presentation, particularly with joint involvement. Intra-articular injections are useful when 1 large joint is involved in the clinical presentation. Specific instructions, however, should be provided to the patient regarding intra-articular injections. Corticosteroids may be used as bridge therapy with DMARDs to avoid long-term adverse events. Some patients also will require continuous therapy to maintain remission of the disease. With continuous therapy, ACR recommends the lowest dose of corticosteroid (eg, prednisone <10 mg daily/d) to control symptoms and reduce the risk of adverse events.6 High doses of corticosteroids also may need to be prescribed as "burst" therapy during exacerbations.


    Table 3: Summary of DMARDs without and with biologic activity
    Disease-modifying antirheumatic drugs. DMARDs are the mainstay of pharmacologic treatment for RA.6–8 These agents consist of agents with nonbiologic or biologic activity. Based on ACR guidelines, DMARDs should be initiated within 3 months of RA diagnosis, allowing for aggressive treatment of the disease.6–8 Based on severity of the disease, particular DMARDs may be recommended and prescribed for an individual or specific patient. DMARDs without biologic activity include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. These agents do not target a specific component of the immune system involved in the pathophysiology of RA but these nonbiologic agents have been shown to improve clinical outcomes. Due to an enhanced understanding in the pathophysiology of RA, therapies with biologic activity have been developed to target a specific component of the immune system. DMARDs with biologic activity include TNF antagonists, IL antagonists, T-cell modulator, and B-cell modulator. Table 3 summarizes DMARDs without and with biologic activity based on therapeutic classification, dosage, and common adverse events with monitoring parameters.6–8,11,12

    PIPELINE AGENTS

    Several therapies for RA are currently being investigated to achieve the unmet needs of its management, such as oral and less expensive medications; the most promising therapies include tofacitinib, fostamatinib, veltuzumab, ofatumumab, apremilast, and secukinumab.13–33

    Tofacitinib is an oral Janus kinase (JAK) inhibitor, which will block the signaling for cytokine proliferation.13 This investigational agent is not a specific inhibitor for a proinflammatory immune system mediator. Tofacitinib, however, targets multiple cytokines to prevent inflammation and further erosion and damage to joints and accessory structures.13 In clinical trials, this JAK inhibitor has been effective to reduce ACR clinical parameters, but each trial has differed in the study design, dosage of tofacitinib, and patient population.14–16 The safety concern with tofacitinib includes long-term immunosuppression due to its mechanism of action on the immune system and chronic dosing characteristics. In addition, cardiac events may be a concern due to the dose-dependent changes in the cholesterol panel.13 It is predicted that the manufacturer will be submitting a new drug application of tofacitinib for FDA approval at the end of the year. If approved, tofacitinib may be a competitor for other DMARDs with biologic activity, but long-term safety will continue to be a concern among practitioners.

    Fostamatinib is a tyrosine kinase inhibitor, which blocks signaling to immune cells. This cell signal inhibition will prevent the proliferation of immune cell mediators to cause further destruction on the joint synovium.17 In a phase 2 multicenter, randomized, double-blind trial, fostamatinib was studied for 6 months among patients who failed methotrexate or other biologic therapies. No significant difference was found in efficacy end points between the doses of fostamatinib (100 mg daily orally twice daily vs 150 mg daily orally once daily), but each dose was superior to placebo. This trial may generate interest to investigate fostamatinib among a subpopulation of patients with an elevated C-reactive protein due to an improvement in clinical outcomes from baseline. The most common adverse events in this trial were nausea and diarrhea at both doses of fostamatinib.18 Phase 3 trials are needed to investigate the use of fostamatinib among certain subpopulations to determine its role as a potential alternate DMARD.

    Veltuzumab and ofatumumab are similar agents to rituximab; these agents are monoclonal antibodies, blocking the CD20 signal to prevent the proliferation of immature and mature B lymphocytes. For veltuzumab, a phase 2 trial has currently been suspended to clarify issues about drug production and filling process; it will be several years before any clinical results are available.19 Ofatumumab is currently approved for chronic lymphocytic leukemia;20 due to its mechanism of action, it will be an alternative agent among patients with RA who have had an inadequate response to methotrexate or other biologic therapies, particularly TNF antagonists.21–23 The disadvantage for ofatumumab would be infusion delivery, which may not be convenient for patients.20 Ocrelizumab is another agent with inhibitory properties of CD20 signal for B-lymphocyte proliferation; however, clinical trials for RA were suspended because ocrelizumab increased the risk of opportunistic infections.24

    Apremilast is a type 4 phosphodiesterase (PDE-4) inhibitor, which is involved with the inhibition of TNF production. This particular type of PDE is expressed on macrophages, lymphocytes, and neutrophils.25 Currently, phase 2 clinical trials are under way to determine the role of this agent in RA.26–28

    Secukinumab is a humanized monoclonal antibody, targeting IL-17A; this specific target inhibits the migration of monocytes and neutrophils around the site of inflammation.29 This particular agent has been investigated as 150 mg daily subcutaneous psoriasis treatment.29 Based on its mechanism of action, secukinumab may be an option for RA due to a potential role on autoimmune diseases.30–33

    UPDATES

    Over recent months, several updates have been reported. In the June issue of the Journal of the American Medical Association, a retrospective cohort study was published regarding the risk of diabetes mellitus with DMARDs among patients with RA.34 The purpose of the study was to evaluate newly diagnosed diabetes among patients with RA or psoriasis on a particular drug regimen. These drug regimens included a TNF antagonist with or without another DMARD, methotrexate without a TNF antagonist or hydroxychloroquine, hydroxychloroquine without a TNF antagonist or methotrexate, or other DMARDs without biologic activity. After an evaluation of 13,905 subjects, an increased incidence rate of new onset of diabetes was found among the various drug regimens: 50.2 for DMARDs without biologic activity, 19.7 for TNF antagonists, 23.8 for methotrexate, and 22.2 hydroxychloroquine per 1,000 person-years. When compared to DMARDs with nonbiologic activity, TNF antagonists and hydroxychloroquine had a lower adjusted risk for diabetes (hazard ratio [HR], 0.62 and 0.54, respectively), whereas methotrexate had an HR of 0.77. This study has several weaknesses, including the lack of randomization with the study design.34 In addition, it is difficult to determine or assess the classification diabetes among participants because the American Diabetes Association (ADA) has changed the diagnostic criteria of diabetes in recent years. In the study, the 2010 ADA guidelines or physician-established criteria defined a diagnosis of diabetes. Finally, no differentiation was made between diabetes classifications (type 1 or type 2). A randomized controlled trial would need to be considered to determine the prevention of diabetes among DMARDs.

    In July 2011, golimumab did not receive an expansion on its product label.35 FDA denied the expansion of the label to inhibition of progressive structural damage, induction of clinical response, and maintenance of clinical presentation, as well as physical function among patients with RA. The denial of its label expansion was due to the lack of clinical trials to support the drug's claims, as well as potential risks regarding golimumab's safety from postmarketing data. Hypersensitivity and anaphylactic reactions have been reported through adverse events reporting to the FDA.35

    In August 2011, FDA approved a subcutaneous formulation of abatacept.36 In addition to an infusion, it will be available as a self-injectable subcutaneous formulation at a fixed dose of 125 mg daily weekly. For patients failing abatacept infusion, an intravenous loading dose will not be required prior to the initiation of weekly injections with abatacept. Patients who have never received abatacept, however, will be required to receive an intravenous loading dose of 10 mg daily/kg prior to initiation of weekly injections.36 Abatacept is now the only DMARD with biologic activity available in both subcutaneous and intravenous formulations.

    For TNF antagonists, a couple of recent updates may impact prescribing by practitioners. First, a recent study published in Rheumatology concluded that there is a higher risk of nonmelanoma skin cancer among patients receiving TNF antagonists.37 The incidence of this particular cancer was 18.9 per 100 patient-years; when compared to a DMARD without biologic activity, the HR was 1.42 for TNF antagonists in the risk of nonmelanoma skin cancer. The greatest risk was among patients of advanced age, male gender, use of NSAIDs or corticosteroids, and prior history of malignancies.37 Although this study demonstrated a causal relationship between TNF antagonists and nonmelanoma skin cancer, it is difficult to make direct conclusions due to the observational study design. However, it may lead to additional patient education in regard to a complete skin examination for patients with RA who are receiving TNF antagonists. TNF antagonists also will get an updated black box warning regarding the risk of bacterial infections.38 Due to postmarketing data, Listeria and Legionella infections will be included in the warning given the consistent information of these infections from adverse event reporting.38 This particular update further emphasizes the importance of patient education prior to the initiation of TNF antagonists, in which all patients should be informed and evaluated for active infections (including bacterial), herpes zoster infection, hepatitis B and C, and active or latent tuberculosis.

    In regard to symptomatic therapy, a recent article in Circulation focused on the determination of the duration of NSAID treatment and relationship with cardiovascular risk among patients with previous myocardial infarction (MI).39 Using nationwide registries, the length of time of first MI and NSAID use was determined by incidence rates. Among approximately 84,000 patients, there was an HR of 1.45 associated with NSAID use and the risk of death and/or recurrent MI. Among the NSAID class, diclofenac was associated with the highest risk (HR, 3.26). Among patients with a history of recurrent or prior MI, NSAIDs should be avoided as both short-and long-term use.39

    CONCLUSION

    For the management of RA, the goal is to slow disease progression and prevent disability, such as loss of physical function. If approved, the emerging therapies for RA may not change the algorithm for RA and approval by FDA may be several years from the present time. Treatment guidelines, however, have been updated to support the use of early, aggressive treatment for a patient with RA. On the downside, economic considerations may be a drawback to existing, advanced therapies and emerging therapies. Additional evidence will be needed given that clinical trials with RA have exhibited wide variability in the patient population, clinical outcomes, and interventions. Long-term benefits remain to be seen, and more comparative studies with standard of care are needed.

    Dr Clements is assistant professor of pharmacy practice, Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, Va.

    Disclosure Information: The author reports no financial disclosures as related to products discussed in this article.

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