Current Therapeutic Agents and Treatment Paradigms for the Management of Rheumatoid Arthritis

Effective management of rheumatoid arthritis (RA) is based on early treatment with pharmacological agents that are appropriate for the degree of disease activity and the presence or absence of indicators of poor prognosis. The 2012 American College of Rheumatology (ACR) treatment recommendations provide clear guidance for pharmacologic management of patients with RA. Although the optimal use of biologic and non-biologic disease-modifying drugs has transformed the treatment of RA to the extent that remission is a reasonable expectation, choice of a particular agent for use in a specific clinical situation remains unclear. Recently, Cochrane reviews as well as a Comparative Effectiveness Review by the Agency for Healthcare Research and Quality have examined the safety and efficacy of these drugs, with a particular emphasis on biologics. The conclusions of these reviews will be examined in the context of the ACR treatment recommendations.

(Am J Manag Care. 2014;20:S136-S144)Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease that usually manifests clinically as symmetric arthritis that affects the small joints of the hands and feet. The characteristic feature of RA is inflammation of the synovium, the membranous lining of the joints, with associated local production of degradative enzymes that eventually destroy joint structures.1 In addition to the pain, disability, and work limitation associated with joint damage, the systemic inflammatory effects of RA also cause and/or contribute to extraarticular comorbidities and psychosocial deficits that further impair health-related quality of life and increase morbidity and mortality in patients with RA compared with the general population.2

During the past 15 years, the treatment of RA has been revolutionized by the development of new disease-modifying antirheumatic drugs (DMARDs), particularly biologic agents. Together with new disease management paradigms, these agents have made remission of disease a realistic goal for the treatment of RA.3 This article will review current therapeutic options for RA, how they are used, and their effectiveness and safety.

Therapeutic Goals of RA Treatment

The advances in the treatment of RA that have been made over the past 15 years are best exemplified by changes in the expectations for therapeutic outcome. Historically, treatment of RA focused on symptom control and pain management. In 2010, an international task force published a series of recommendations for a treat-to-target management approach to RA. This treatment strategy emphasized that the primary target for treatment of RA should be a state of clinical remission. Although low disease activity (LDA) may be an acceptable alternative therapeutic objective, particularly in patients with established, long-standing disease and considerable joint damage, this goal should be secondary to achieving remission. Until the desired outcome is reached, therapy should be adjusted as often as monthly in patients with high/moderate disease activity; adjustments should be made every 3 to 6 months in patients with sustained LDA or remission.3 This strategy was subsequently incorporated into the European League Against Rheumatism (EULAR) recommendations for the management of RA in 2010 and 2013, which also emphasized that treatment with synthetic DMARDs should begin as soon as the diagnosis of RA is made.4,5 Similarly, in the most recent American College of Rheumatology (ACR) guideline for the management of RA, remission or LDA is the goal of treatment in both early (disease duration <6 months) and established RA.6

The issue of what constitutes remission during RA treatment has evolved over time. In the first attempt by the ACR to define remission in RA, a distinction was made between “complete remission,” which implied a total absence of inflammation and immunological activity related to RA that would be difficult to measure, and “clinical remission,” a state that could be defined using conventional clinical measurements.7 The criteria for remission that were initially developed have not been widely used in clinical trials, both because some of the elements of the criteria are no longer assessed and because the criteria were so stringent that very few patients achieved remission.8

With the development of validated indices of disease activity such as the Disease Activity Score in 28 joints (DAS28), an attempt was made to establish a level of disease activity that could define remission. In an analysis of a large cohort of patients with RA who were receiving treatment, DAS28 scores (calculated using the erythrocyte sedimentation rate [ESR] as an index of inflammation) were validated against the 1981 ACR remission criteria. Based on the results of the analysis, clinical remission was defined as DAS28 less than 2.6.9 Subsequent studies have suggested that this degree of disease activity is not sufficiently stringent to define remission.10,11 The value of DAS28 indicative of remission also differs if the DAS28 is calculated using C-reactive protein (CRP) as the index of inflammation rather than ESR. When CRP is used, remission is defined as DAS28 less than 2.3.12 Most recently, a collaborative committee of the ACR and EULAR assessed the use of core set measures including, at a minimum, joint counts and levels of an acute-phase reactant to define remission. Based on these analyses, the committee has suggested 2 possible approaches to defining clinical remission in RA clinical trials. A patient can be considered to be in remission when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all less than 1 or, alternatively, when the score on the Simplified Disease Activity Index (SDAI) is less than or equal to 3.3.8 The SDAI is the numerical sum of 5 parameters that are measured during assessment of RA (tender and swollen joint counts, physician and patients global assessments of disease, and CRP).13

ACR Recommendations for Treatment of RA

A list of the medications currently used for the management of RA in the United States is shown in Tables 1 to 3. The available medications include corticosteroids, 4 conventional DMARDs, 1 targeted DMARD, and 9 biologic DMARDs (5 tumor necrosis factor [TNF] inhibitors and 4 other biologic DMARDs that act at other points in the inflammatory cascade).14,15

Tofacitinib is the most recent addition to the list of available agents for the treatment of RA, having received approval from the US Food and Drug Administration (FDA) in November, 2012. Tofacitinib is an oral inhibitor of janus kinase (JAK), an intracellular enzyme in a pathway that transmits signals from cytokine or growth factor—receptor interactions on the cellular membrane to the nucleus, where they can alter genomic expression.15 Other JAK inhibitors are in development. Other intracellular kinases that are potential targets for RA therapy include p38 mitogen-activated phosphokinase (MAPK) and spleen tyrosine kinase (Syk).16 Development of fostamatinib, the Syk inhibitor that was furthest along in the clinical testing process, was suspended in 2013 based on marginal efficacy results in phase 3 clinical trials.

Corticosteroids are used for management of the symptoms associated with a variety of inflammatory, autoimmune conditions. Corticosteroids are synthetic forms of cortisol that act by binding to steroid-specific receptors in the cytoplasm of cells, inhibiting the movement of inflammatory cells, neutrophil function, and prostaglandin production. In patients with RA, corticosteroids are prescribed based on their ability to reduce signs and symptoms of inflammation, joint pain, and swelling.14

Although there has been some renewed interest in using low-dose corticosteroids as a bridge to DMARD therapy in early RA, use of these drugs is limited by their adverse event profile. In a study that compared adverse 5-7.5, mg, or >7.5 mg daily) with adverse events in control subjects receiving no corticosteroids, investigators found a relationship between dosage and adverse events. Results showed there was a linear, dose-dependent increase in subcutaneous hematomas, leg edema, fungal infection, shortness of breath, and sleep disturbances. In addition, at dosages greater than 7.5 mg/day, increases in depression, glaucoma, and increased blood pressure were recorded.17

The ACR recommendations for the use of DMARDs are divided into 2 sections: treatment of early RA, defined as disease duration of less than 6 months, and treatment of established RA.6 The use of early RA as a separate treatment category is based on evidence indicating that delay in treatment is a strong prognostic factor for poor treatment response and that early, aggressive treatment increases the probability of effective response to treatment. One of the earliest indicators of the importance of treatment timing in determining therapeutic response was a meta-analysis of 14 randomized controlled trials (RCTs) that analyzed factors that affected the response to treatment (defined as achievement of an ACR 20 response) of approximately 1400 patients with RA. Disease duration at the initiation of treatment was one of the strongest predictors of response to therapy, with longer duration predicting a poorer response. The ACR20 response rate, regardless of the specific DMARD used, was 53% in RA patients with disease duration 1 year or less compared with 35% to 43% of those with a disease duration greater than 1 year.18

Early RA

The benefits of treating very early RA (≤4 months disease duration) were tested in a post hoc analysis of data from the Combination or Methotrexate and Etanercept (COMET) study. In this study, the response in patients with RA to treatment in terms of LDA (DAS28 <3.2) and remission (DAS 28 <2.6 or SDAI ≤3.3) was assessed after 52 weeks in patients with very early RA compared with patients with early RA (>4 months but <2 years). Combination therapy with etanercept and methotrexate (MTX) in patients with very early disease resulted in improvements in LDA and remission relative to early therapy (79% vs 62%; P = .014 and 70% vs 48%; P =.004, respectively). In patients receiving MTX alone, this effect was not seen. Patients with early RA and very early RA had similar rates of LDA and remission. No radiographic evidence of progression was found in 80% of the group receiving combination therapy, regardless of duration of RA. However, among patients who received MTX monotherapy, a higher percentage of patients with very early disease had no radiographic progression when compared with patients with early disease (73.9% vs 50%; P <.01). The authors concluded that very early treatment events in patients receiving corticosteroids (ie, <5 mg, with combined MTX and etanercept improves clinical outcomes compared with MTX monotherapy.19 These observations concerning the efficacy of early treatment of RA with DMARDs are particularly pertinent in light of one study’s finding that 41% of patients received a DMARD within 6 months of symptom onset. Time to referral to a rheumatologist represented the largest component of this delay.20

In the ACR algorithm for the treatment of early RA (disease duration <6 months), the choice of initial therapy is based on the level of disease activity (low, moderate, or high) and the presence or absence of features of poor disease prognosis. The level of disease activity is based on cut points of various instruments that are commonly used to measure disease activity. Thus, for example, if the DAS28 is used for assessment of disease activity, low disease activity would be defined as a score of 2.6 to 3.2; moderate disease activity, 3.2 to 5.1; high disease activity, greater than 5.1. Other instruments for which cut points are provided include the Routine Assessment of Patient Index Data (RAPID-3), Clinical Disease Activity Index (CDAI), and the SDAI. Designation of a patient as having features of poor prognosis is based on the presence of 1 or more of the following features: functional limitation, extra-articular disease, RA vasculitis, presence of rheumatoid factor, or anti-cyclic citrullinated peptide antibodies, and bony erosions on x-rays.6

For patients with early disease without features of poor prognosis, the ACR recommends DMARD monotherapy, usually initiated with MTX, regardless of the level of disease activity. For patients with moderate disease activity and features of poor prognosis, treatment with double or triple DMARD therapy is recommended. Patients with high disease activity but no features of poor prognosis should be treated with DMARD monotherapy or combination therapy with hydroxychloroquine (HCQ) and MTX. The most at-risk category pertains to patients with high disease activity and features of poor prognosis. In these patients, a TNF inhibitor, with or without MTX, or double or triple conventional DMARD therapy should be initiated.6

The ACR treatment recommendations indicate that all patients should be reassessed after 3 months, and therapy should be escalated if moderate or high disease activity persists. The only exception to this rule is when a patient is treated with a biologic that is not a TNF inhibitor. Because of the relatively slow onset of action with these biologics, reassessment is recommended at 6 months after initial treatment.6 The treat-to-target recommendations indicate that in patients with high disease activity, there is a need for frequent assessment of the disease status (eventually as often as monthly) to adapt treatment accordingly. When patients reach LDA and sustain this state, less frequent evaluations (ie, every 3-6 months) may be sufficient.3

Established RA

In the ACR recommendations for treatment of established RA (disease duration >6 months), patients with low disease activity and no features of poor prognosis who are receiving DMARD monotherapy should be reassessed after 3 months unless the patient is receiving a biologic that is not a TNF inhibitor. In this case, reassessment after 6 months is recommended based on a longer time to peak effect. If disease activity has increased to moderate or severe over this period, then MTX, HCQ, or leflunomide should be added. If disease activity is still high after another 3 months of treatment with MTX or a MTX/DMARD combination, another DMARD should be added or the non-MTX DMARD should be switched. If, at the next assessment, disease activity is still elevated, a TNF inhibitor should replace or be added to the current regimen. If the TNF inhibitor has to be terminated because of incomplete response or adverse events, it can be replaced with another TNF inhibitor or with another class of biologic.6

In patients with moderate or high disease activity or patients with low disease activity but with features MTX monotherapy or MTX/DMARD combination therapy, treatment should be replaced or supplemented with a TNF inhibitor or abatacept. Failure to respond to therapy (defined as continued high or moderate disease activity) at the next assessment period should result in switching to another TNF inhibitor or to another class of biologic.6

Switching Therapies

Guidance about switching among biologic agents in the ACR recommendations is largely determined by the reason necessitating the switch. If a patient fails to respond to a biologic or subsequently loses responsiveness during treatment, a switch to another TNF inhibitor or to another class of biologics is recommended. A patient with high disease activity who fails treatment with a TNF inhibitor because of a serious adverse event should be switched to another class of biologic. If the adverse event is not serious, the patients may be switched to another TNF inhibitor or another class of biologic. A patient with moderate or high disease activity who fails a non-TNF-related biologic because of an adverse event, either serious or non-serious, can be switched to either another non-TNF-related biologic or to a TNF inhibitor.6

Efficacy and Safety of DMARDS

DMARDs in general, and MTX in particular, are mainstays of current recommendations for the treatment of RA because of their ability to slow or halt the progression of disease and are the first drugs recommended for all patients with RA.5,6 The current EULAR recommendations state that treatment with DMARDs should begin as soon as diagnosis of RA is made.5

A Comparative Effectiveness Review (CER) of drug therapy options in RA was recently conducted by Agency for Healthcare Research and Quality (AHRQ).14 This analysis included a systematic review of the literature related to DMARD treatment of RA as well as a metaanalysis of comparative trials. The AHRQ review and meta-analysis ultimately included 258 published articles reporting on 211 studies: 31 head-to-head RCTs, 1 headto- head nonrandomized controlled trial, 44 placebocontrolled trials, 28 meta-analyses or systematic reviews, and 107 observational studies. The efficacy analyses focused on head-to-head trials and prospective cohort studies comparing one drug with another. For biologic DMARDs, placebo-controlled, double-blind randomized controlled trials were also included. All included studies had a sample size at least 100 and duration of at least 3 months. All studies used drug doses that were within the recommended dosing range or equivalent to recommended doses. Strength of evidence was also assessed for important outcomes.14

The majority of the CER’s findings were based on indirect comparisons and cited as having a low strength of evidence, largely because of the limited number of head-to-head clinical trials. Efficacy comparisons with a moderate or high strength of evidence included the following:

• ACR20 response, disease activity scores, radiographic changes, and improvement in functional capacity are equivalent in patients with RA treated with MTX and sulfasalazine (SSZ).
• The effects of combination therapy with SSZ and MTX on ACR20, radiographic changes, and functional capacity do not differ from the effects seen with either drug used as monotherapy.
• Addition of prednisone to an oral DMARD results in better improvement in functional capacity than oral DMARD alone.
• In patients with early RA, clinical responses to etanercept, adalimumab, or MTX were similar, but radiographic outcomes were better with biologic DMARDs than with MTX.
• Clinical outcomes in patients with RA treated with MTX in combination with a biologic are better than in patients treated with biologic monotherapy.
• Clinical response rates, functional capacity, and quality of life in patients with RA are improved more by treatment with biologic and MTX combination therapy than with MTX alone.14

With regard to selection of a specific biological agent, the authors of the CER noted that there have been few direct comparisons to govern this choice. With the exception of anakinra, which was determined to be less effective, the biologics were found to have roughly equivalent efficacy using validated RA outcome measures.¹⁴ Similarly, a Cochrane review of the use of biologics in RA concluded that the efficacy of all agents, defined as achievement of ACR50, was similar with the exception of anakinra, which was less effective.²¹

The efficacy and safety of the TNF inhibitors (adalimumab, certolizumab, etanercept, golimumab, infliximab) was assessed in a 2012 meta-analysis that included 26 RCTs.²² As a group, TNF inhibitors had a risk ratio (RR) of 4.07 (95% CI, 2.70-6.13) for achieving ACR50 compared with controls. All the individual TNF inhibitors of poor prognosis who fail to respond to 3 months of provided significantly better odds for achieving ACR50, with the exception of golimumab. Additionally, TNF inhibitor combination therapy with MTX was more effective for achieving ACR50 after 6 months than MTX alone (RR, 3.37; 95% CI, 2.38-5.98). A comparison of TNF inhibitor monotherapy with MTX monotherapy favored the TNF inhibitors but did not reach statistical significance. High doses of TNF inhibitors (relative to normal doses) did not improve ACR50 after 6 months (RR, 1.02; 95% CI, 0.9-1.15).²²

The safety of biologics has been analyzed in 2 recent Cochrane reviews.21,23 In the first review, which considered both the efficacy and safety of biologics for RA, patients treated with adalimumab were more likely to withdraw from therapy than patients treated with etanercept (odds ratio [OR], 1.89; 95% CI, 1.18-3.04; P = .009). Withdrawal was also more likely with anakinra than etanercept (OR, 2.05; 95% CI, 1.27-3.29; P = .003), and less likely with etanercept than with infliximab (OR, 0.37; 95% CI, 0.19-0.70; P = .002).21

The second Cochrane review dealt specifically with adverse events associated with the use of biologics. The median duration of the RCTs included in the analysis was 6 months and 13 months for open-label extensions. Comparisons were made of adverse events during treatment with a standard dose of a biologic versus the control. As a group, biologics were associated with a statistically significant higher rate of total adverse events (OR, 1.28; 95% CI, 1.09-1.50; P = .00013), withdrawals due to adverse events (OR, 1.47; 95% CI 1.20-1.86), serious infections (OR, 1.37; 95% CI, 1.04-1.82), and tuberculosis reactivation (OR, 4.68, 95% CI, 1.18-18.60). In an analysis of safety of individual agents compared with controls, infliximab treatment was associated with a significantly higher risk of of total adverse events (OR, 1.55; 95% CI, 1.01-2.35) and more treatment withdrawals (OR, 2.34; 95% CI, 1.40-4.14) compared with the control treatment. Treatment with certolizumab pegol was associated with a significant risk of serious adverse events (OR, 1.57; 95% CI, 1.06-2.32) and serious infections (OR, 4.75; 95% CI, 1.52-18.45) compared with the control treatment. Treatment with anakinra was also associated with a significant risk of serious infections compared with the control treatment (OR, 4.05; 95% CI, 1.22-16.84).23

None of the analyses mentioned previously include tofacitinib, a new oral DMARD for RA that was approved for use by the FDA in 2012. The efficacy of tofacitinib was tested in a series of clinical trials that included patients with inadequate responses to DMARDs, MTX, and/or TNF inhibitors. In patients receiving 5 mg of tofacitinib daily, ACR responses after 3 months ranged from 41% to 59% for ACR20, 26% to 31% for ACR50, and 11% to 15% for ACR70. All responses were significantly higher than those seen in placebo-treated patients. Similar results were noted after 6 months of treatment.15

The prescribing information for tofacitinib includes a warning for possible serious infections, and lymphoma and other malignancies. The most common serious adverse event during treatment with tofacitinib was serious infection. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infections. In the 7 controlled trials, serious infections were reported in 1 patient who received placebo (0.5 events per 100 patient-years) and in 11 patients who received tofacitinib 5 mg or 10 mg twice daily (1.7 events per 100 patient-years) during the exposure period (0 to 3 months).15

Formulations and Delivery Systems

Although current treatment options for RA offer the potential for reducing disease activity, no single agent is effective in all patients. All treatment options should be available to all patients to increase the probability of finding the best agent for a specific patient. While considering a patient’s disease status and overall health should be paramount when choosing a therapy, differences in the routes of administration can also affect patient acceptance and treatment continuation. Considerations such as these have led to the development of both oral and subcutaneous formulations for delivery of DMARDs such as MTX. Alternative formulations have been developed for 2 intravenous biologics for RA, tocilizumab and abatacept, that allow for subcutaneous injection of these agents.24,25 A subcutaneous formulation offers patients with RA an additional, potentially more convenient administration option that can be used at home. The ease and convenience of subcutaneous injections has also been improved by the development of disposable autoinjection pens for MTX26 and for several of the biological DMARDs (eg, adalimumab).²⁷

Biosimilars

Biosimilars, nonproprietary versions of biological drugs whose patent life has expired, are emerging as potentially important additions to the roster of antirheumatic drugs. Specific regulatory protocols for the development and approval of these drugs have been developed by both the European Medicines Agency and the FDA. In both cases, approval is based on demonstration of bioequivalent effect of the biosimilar and the innovator drug in a clinical trial.²⁸ Based on such trials, CT-P13 (Inflectra), a biosimilar of infliximab, was approved for use in the European Union in 2013.²⁹ Biosimilars for etanercept and rituximab are also in development.^30,31 At present, however, biosimilars are not available in the United States.

Conclusions

The 2012 ACR treatment recommendations provide clear guidance for pharmacologic management of patients with RA. Although early treatment should be emphasized for all patients, it is particularly important that patients with high-risk characteristics receive aggressive therapy with a combination of MTX and a biologic, or with DMARD combination therapy, to prevent progression of disease. While the various biologic agents can be differentiated by mechanism of action, dosage, dose frequency, and route of administration (Table 3), differentiation in terms of efficacy remains unclear. Finally, remission, or alternatively, LDA, should be the goal of treatment in every patient.Author affiliations: Weill Medical College of Cornell University, New York, NY, and Hospital for Special Surgery, New York, NY.

Funding source: This activity is supported by an educational grant from Antares Pharma, Inc.

Author disclosure: Dr Gibofsky reports serving as a consultant for AbbVie, Amgen, Antares Pharma, Inc, Celgene, Iroko, and Pfizer. Dr Gibofsky also reports serving on a speaker’s bureau for AbbVie, Amgen, Antares Pharma, Inc, Celgene, Iroko, Pfizer, and UCB. He reports stock ownership with AbbVie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Pfizer, and Regeneron.

Authorship information: Concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and supervision.

Address correspondence to: Allan Gibofsky, MD, JD, FACP, FCLM, 535 E 70th St, New York, NY 10021. E-mail: GibofskyA@hss.edu.

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