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MEDICAL JOURNAL REVIEW

Strategies for Achieving Treatment Goals in Rheumatoid Arthritis


Introduction

The European League against Rheumatism (EULAR) recently updated their 2010 recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (DMARDs),[1] and the American College of Rheumatology (ACR) is in the process of updating their 2012 guidelines.[2] Although these guidelines are useful, the recommendations are broad, and clinicians may still have challenges selecting from among the many treatment options for individual RA patients in the real-world practice setting. With results from numerous clinical trials published during the past few years, it can be challenging to wade through the large amounts and different types of data to know how to compare benefits and limitations to choose the right treatment for a patient at different stages of RA.

Medscape:Thank you, Dr Kavanaugh, for joining us in this expert interview on the challenges in the management of RA. To begin, let's consider the updated ACR and EULAR guideline recommendations and recent studies as they relate to certain patient categories. Let's start with a patient who has early RA, with moderate-high disease activity and features of poor prognosis (Figure 1).

Dr Kavanaugh: A good consensus exists that the place to start therapy is with methotrexate (MTX), barring any contraindications to its use. MTX can be used as monotherapy or in combination with other agents. In the Treatment of Early Arthritis (TEAR) trial, patients with early poor-prognosis RA were randomly assigned to receive MTX monotherapy, with an option to step-up to combination therapy (with either MTX/etanercept [ETN] or to triple therapy with MTX + sulfasalazine (SSZ) + hydroxychloroquine) or immediate combination therapy.[3] At 102 weeks, patients who started MTX monotherapy or combination therapy had similar Disease Activity Score 28 (DAS28)-erythrocyte sedimentation rate scores. Twenty-eight percent of patients receiving MTX monotherapy achieved low disease activity (LDA) and did not step up to combination therapy, highlighting the efficacy of initial MTX monotherapy for a subset of patients.

Figure 1. American College of Rheumatology Recommendations Update for the Treatment of Established Rheumatoid Arthritis, 2012.

DMARD = disease-modifying antirheumatic drug; HCQ = hydroxychloroquine; LEF = leflunomide; MTX = methotrexate; RA = rheumatoid arthritis; TNF = tumor necrosis factor.
* Definitions of disease activity are discussed in Tables 2 and 3 and Supplementary Appendix 4 (available in the online version of article) and were categorized as low, moderate, or high. † Features of poor prognosis included the presence of 1 or more of the following: functional limitation (eg, Health Assessment Questionnaire score or similar valid tools), extraarticular disease (eg, presence of rheumatoid nodules, RA vasculitis, Felty's syndrome), positive rheumatoid factor or anti-cyclic citrullinated peptide antibodies, and bony erosions by radiograph.
‡ Combination DMARD therapy with 2 DMARDs, which is most commonly MTX based, with few exceptions (eg, MTX + HCQ, MTX + LEF, MTX + sulfasalazine, sulfasalazine + HCQ), and triple therapy (MTX + HCQ + sulfasalazine).
§ Reassess after 3 months and proceed with escalating therapy if moderate or high disease activity in all instances except after treatment with a non-TNF biologic (rectangle D), where reassessment is recommended at 6 months owing to a longer anticipated time for peak effect.
¶ LEF can be added in patients with low disease activity after 3 to 6 months of minocycline, HCQ, MTX, or sulfasalazine.
# If after 3 months of intensified DMARD combination therapy or after a second DMARD has failed, the option is to add or switch to an anti-TNF biologic.
** Serious adverse events were defined per the US Food and Drug Administration (FDA; see below); all other adverse events were considered nonserious adverse events.
†† Reassessment after treatment with a non-TNF biologic is recommended at 6 months due to anticipation that a longer time to peak effect is needed for non-TNF compared with anti-TNF biologics.
‡‡ Any adverse event was defined as per the FDA as any undesirable experience associated with the use of a medical product in a patient. The FDA definition of serious adverse event includes death, life-threatening event, initial or prolonged hospitalization, disability, congenital anomaly, or an adverse event requiring intervention to prevent permanent impairment or damage.
Singh JA, et al.[2]

In the worldwide OPTIMA study, MTX-naive patients were randomly assigned to receive either adalimumab (ADA) with MTX or placebo with MTX.[4,5] In this study, combination therapy (ADA+MTX) was significantly superior to MTX monotherapy in clinical, radiographic, and functional outcomes, but it was also associated with more serious infections and deaths.[4] Patients in the combination treatment group who achieved stable LDA were able to withdraw or continue receiving ADA for the second 52 weeks of the study; patients in the MTX monotherapy group who had an inadequate response were offered ADA+MTX.[5] A higher proportion of patients in the combination therapy group achieved the target LDA than did patients receiving MTX monotherapy; however, in both groups, treating to a stable LDA target led to improved clinical, functional, and structural outcomes.

The speed and magnitude of response to initial treatment predict long-term outcomes among patients with early RA.[6] In the PREMIER study, patients were randomly assigned to ADA monotherapy, MTX monotherapy, or ADA+MTX for 2 years.[6,7] Intensive combination therapy led to greater clinical, functional, and radiographic outcomes by 3 months compared with in patients having a delayed response to initial MTX monotherapy. The High Induction Therapy With Anti-Rheumatic Drugs (HIT HARD) study also compared ADA+MTX with MTX monotherapy in DMARD-naive patients with active early RA and found a greater reduction in DAS28 and other secondary outcomes with combination therapy at 24 weeks.[8] All patients in this trial then received MTX monotherapy from week 24 to 48; although the difference in clinical outcomes was not statistically significant, initial combination therapy led to greater reduction in radiographic progression. In comparison, combination treatment with ETN and MTX was not found to be superior to MTX monotherapy with regard to tender or swollen joints at week 52 in the EMPIRE trial; however, combination therapy led to earlier achievement of clinical response (including DAS28-C-reactive protein < 2.6).[9]

So you can see, these are complex decisions, but they are aided by a key aspect of both ACR and, particularly, EULAR recommendations; namely, the strong recommendation to regularly assess patient response to treatment. Clinicians should plan on frequent evaluations; some suggest every 3 months, although I think most rheumatologists will monitor patients more frequently, particularly when initiating a patient on treatment.

Medscape:How might you treat the patient with early RA and moderate disease activity who is a nonresponder to MTX monotherapy?

Dr Kavanaugh: We are currently fine-tuning the use of MTX. Before saying treatment has failed, I think we want to make sure we have really optimized the regimen, including titrating the dose toward 20 mg (or higher) and/or giving it subcutaneously.[10] Someone who has not responded to an optimized MTX regimen still has options, including adding additional DMARDS, such as hydroxychloroquine or leflunomide, or using "triple therapy" (MTX + hydroxychloroquine + SSZ). Although it is used less frequently, there are good data supporting the use of cyclosporine A.[11-13] For many of us, the strategy at this point depends on the patient's response to MTX. Most physicians would continue to use MTX if the patient has had some response. For patients who really did not respond to initial MTX therapy, you could make a case for just switching from MTX to an alternative DMARD.

Another issue addressed in the ACR recommendations concerns what else you could add in patients with bad prognostic factors. We frequently consider introducing a biologic agent, probably one of the tumor necrosis factor (TNF) inhibitors, because rheumatologists have had many years more experience with them than with non-TNF-biologic agents.[14] In the Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan (JESMR) study, adding ETN to MTX was superior to switching from MTX monotherapy to ETN monotherapy.[14] You might also consider one of the other biologics, including the B cell-targeted therapy rituximab (RTX), the T cell-targeted therapy abatacept (ABA), the interleukin 6 blocker tocilizumab (TCZ), and even the new oral JAK inhibitor tofacitinib.[15-20] Tofacitinib is a novel Janus kinase inhibitor that is indicated for patients with moderate to severe RA who have an inadequate response or intolerance to MTX. When used in combination with MTX, it led to rapid and clinically meaningful improvements in signs and symptoms of RA.[21] Recent studies such as SERENE[15] and LITHE [16] demonstrated the benefits of adding a biologic agent (RTX or TCZ, respectively) to MTX for patients with a partial response to MTX monotherapy. In both studies, patients who were switched to combination therapy had significantly improved outcomes compared with those who continued receiving MTX monotherapy.

Medscape:Now let's talk about the patient with established RA who becomes intolerant or nonresponsive to MTX and TNF-inhibitor therapy (Figure 2).

Dr Kavanaugh: It would depend on the specific tolerance issue. For example, you would switch agents if an adverse effect were involved, but if it was tuberculosis, I would be concerned it might be related to the TNF as a mechanism.[22] In this case, I likely would not go with another TNF inhibitor but would probably switch to one of the other biologics. In contrast, it would be reasonable to try a different TNF inhibitor if intolerance were caused by an injection reaction. For a patient who did well on a TNF inhibitor and then gradually lost response, switching to a second TNF inhibitor would be reasonable. If they had absolutely no response, I think you could make a case for switching to an alternative mechanism. It really depends on the trajectory of clinical benefit and also the tolerance issues.

Figure 2. American College of Rheumatology Recommendations Update for the Treatment of Established Rheumatoid Arthritis, 2012.

DMARD = disease-modifying antirheumatic drug; HCQ = hydroxychloroquine; LEF = leflunomide; MTX = methotrexate; RA = rheumatoid arthritis; TNF = tumor necrosis factor.
* Definitions of disease activity are discussed in Tables 2 and 3 and Supplementary Appendix 4 (available in the online version of article) and were categorized as low, moderate, or high.
† Features of poor prognosis included the presence of 1 or more of the following: functional limitation (eg, Health Assessment Questionnaire score or similar valid tools), extraarticular disease (eg, presence of rheumatoid nodules, RA vasculitis, Felty's syndrome), positive rheumatoid factor or anti-cyclic citrullinated peptide antibodies, and bony erosions by radiograph.
‡ Combination DMARD therapy with 2 DMARDs, which is most commonly MTX based, with few exceptions (eg, MTX + HCQ, MTX + LEF, MTX + sulfasalazine, sulfasalazine + HCQ), and triple therapy (MTX + HCQ + sulfasalazine).
§ Reassess after 3 months and proceed with escalating therapy if moderate or high disease activity in all instances except after treatment with a non-TNF biologic (rectangle D), where reassessment is recommended at 6 months owing to a longer anticipated time for peak effect.
¶ LEF can be added in patients with low disease activity after 3 to 6 months of minocycline, HCQ, MTX, or sulfasalazine.
# If after 3 months of intensified DMARD combination therapy or after a second DMARD has failed, the option is to add or switch to an anti-TNF biologic.
** Serious adverse events were defined per the US Food and Drug Administration (FDA; see below); all other adverse events were considered nonserious adverse events.
†† Reassessment after treatment with a non-TNF biologic is recommended at 6 months due to anticipation that a longer time to peak effect is needed for non-TNF compared with anti-TNF biologics.
‡‡ Any adverse event was defined as per the FDA as any undesirable experience associated with the use of a medical product in a patient. The FDA definition of serious adverse event includes death, life-threatening event, initial or prolonged hospitalization, disability, congenital anomaly, or an adverse event requiring intervention to prevent permanent impairment or damage.
Singh JA, et al.[2]

The ADACTA study randomly assigned patients who were intolerant to MTX or for whom continued treatment with MTX was inappropriate to monotherapy with either TCZ or ADA and found that TCZ monotherapy was superior to ADA monotherapy in reducing the signs and symptoms of RA.[23] In the AMPLE trial, biologic-naive patients with an inadequate response to MTX had either subcutaneous ABA or ADA added to their regimen.[24] The 2 combination treatments were similarly efficacious, based on clinical, functional, and radiographic outcomes, as well as frequency of adverse events.[24]

Using data from a Norwegian 5-center register (NOR-DMARD) register, Lie et al compared the effectiveness of adding a synthetic DMARD or a TNF inhibitor to MTX in patients with RA who had an inadequate response to MTX monotherapy; in addition, the study examined outcomes of patients who were switched to MTX+TNF inhibitor for whom the MTX+DMARD combination had failed.[25] The combination of MTX+TNF inhibitor was associated with better effectiveness at 3 and 6 months, as well as 2-year drug survival, compared with MTX+DMARDs. Triple therapy was somewhat more effective than the MTX+DMARD combination but was generally less effective than MTX+TNF inhibitor. However, patients who received MTX+TNF inhibitor as a third step after failing on 2 MTX+DMARD regimens were likely to have less favorable disease states at 3 months than patients who were directly switched from MTX to MTX+TNF inhibitor.[25]

In the prospective, global, real-life SWITCH-RA study, patients who had an inadequate response to a previous TNF inhibitor were switched to either RTX or an alternative TNF inhibitor.[26] A majority (75%) of the patients had discontinued the first TNF inhibitor for inefficacy; 24% had discontinued for intolerance. Patients who switched to RTX had significantly improved clinical effectiveness (DAS28-ESR excluding patient's global health component; DAS28-3-ESR) compared with patients who received a second TNFi, particularly among patients who were either seropositive or who switched because of inefficacy.[26]

Medscape: Can you address how you might treat a patient with established RA who becomes nonresponsive to a second TNF inhibitor?

Dr Kavanaugh: For the patient who becomes nonresponsive to a second TNF inhibitor, we need to work with the patient and examine factors that might affect their treatment choice. We know convenience is an important consideration, but cost can also be an issue to the patient. It is important to know the trajectory. For example, if the patient had gone on a second TNF inhibitor, did well for a year, and then stopped responding to it, I may well go to a third TNF inhibitor, depending on how well they had initially responded. If they tried the second agent and had a poor response, I would switch to an agent with a different mechanism of action.

A study using the Swedish national register of patients with RA examined those patients who switched to a second TNF inhibitor after discontinuing a first TNF inhibitor.[27] The study noted that approximately 50% of patients who had begun treatment with infliximab (INF), ADA, or ETN discontinued, and 1 in 3 patients discontinued within 2 months to a second TNF inhibitor. Among those who switched to another TNF inhibitor, approximately 35% achieved LDA or remission at 6 months.[27]

A recent trial examined nonresponders to TNF-inhibitors who were randomly assigned to either a cycling treatment with a second TNF inhibitor (a cycling strategy) or to treatment with an agent with a different mechanism of action, such as ABA, RTX, or TCZ (swap strategy).[28] Patients in the swap strategy group had significantly higher drug survival than did patients in the cycling group, leading investigators to conclude that the best option for managing TNF inhibitor nonresponders might be swapping to an agent with a different mechanism of action, regardless of the reason for the initial TNF inhibitor nonresponse.[28] Similarly, a study investigating the cost-effectiveness of sequencing biologic treatments after failure of an initial biologic treatment found that swapping strategies may be more cost-effective than cycling sequences.[29]

Medscape:Let's now move on to the patient who has achieved and is maintaining remission on combination DMARD and biologic therapy. Is it possible to withdraw therapy?

Dr Kavanaugh: There are actually a fair number of studies that look at this. Unfortunately, the studies are heterogeneous, so there is not an absolute, consistent answer. And I think the answer is that it might be possible. In the United States, patients may be interested in tapering or discontinuing therapy for several reasons, but a very prominent reason is cost. In fact, patients will often be the driver of this particular decision, telling me they have either totally stopped or extended their dosing interval (eg, taking a drug every 2 weeks instead of every week). There is no doubt cost is an important issue. Another issue concerns patient preference: People do not like being sick, and some patients equate taking medicines with being sick. Therefore, they reason, not taking medication suggests you are not sick. In either of these cases, withdrawing treatment is a very personal decision, driven by the patient.

I have decided to withdraw patients from treatment on occasion, especially when the patient is in a very deep or a very strong remission and has been there for some time. There are limited data that support this action. For example, in the OPTIMA study discussed earlier, patients who had an initial response to combination therapy with MTX+ADA had comparable outcomes whether they continued receiving the combination treatment or withdrew ADA.[6] Similarly, the Behandel Strategieen (BeSt) study examined the benefit of treat-to-target strategies, comparing sequential monotherapy (beginning with MTX); step-up to combination therapy (also starting with MTX+INF); initial combination therapy with MTX, SSZ, and prednisone; or initial combination therapy with MTX and INF.[30] Nearly two thirds of the patients who started initial treatment with MTX+INF were able to discontinue INF treatment, and 25% of patients who started delayed INF were able to eventually discontinue INF. In all, half of the patients who continued with MTX were able to permanently stop INF therapy.[30]

Realistically, there is not a single definitive answer as to who might be able to withdraw from therapy. There are data suggesting it may be easier in people with earlier onset of disease, and possibly among people who are in very deep remission. I think it is worthwhile to try it, and I think it does seem that some people are able to do it.

Medscape:Finally, can you please talk about the challenges in interpreting and generalizing the data and findings from registries versus double-blind, placebo-controlled, randomized trials?

Dr Kavanaugh: A double-blind, randomized, placebo-controlled clinical trial is the gold standard for efficacy, and even for safety determination. With this approach, you get a very thorough assessment of efficacy, and it can be a very good source of information. However, there are certain disadvantages to these types of trials. One is the inherent possibility for selection bias, because not everybody will get into a clinical trial (often because of comorbidities) and not everybody wants to participate in a clinical trial. In addition, study populations are generally smaller than is seen with registry studies. As a consequence, you may not be able to extrapolate the results from clinical trials to every patient you see in clinic.[31] Comparing results from clinical trials can be difficult, as different trials may use different outcomes measures, inclusion/exclusion criteria, and approaches for analyzing and reporting the results.[32]

The other limitation associated with RCTs concerns the length of treatment and/or follow-up. In real life, we see patients over the course of years, which is not feasible with a clinical trial. Registries typically include longer durations of treatment/follow-up, as well as very large numbers of patients, enabling investigators to look more closely for contributing factors or to look at subsets of patients. Current registries include the Consortium of Rheumatology Researchers of North America, Inc. (CORRONA) registry, Canadian Early Arthritis Cohort (CATCH), Antirheumatic Therapies in Sweden (ARTIS) registry, Dutch Rheumatoid Arthritis Monitoring (DREAM) registry, the German biologics register Rheumatoid Arthritis Observation of Biologic Therapy (RABBITT), the British Society for Rheumatology Biologics Register (BSRBR), the nationwide Danish registry DANBIO, NOR-DMARD, the Spanish Registry of Biologics in Rheumatology (BIOBADASER), the Swiss RA registry (SCQM-RA), and many other registries worldwide. For example, using the DREAM registry of 2044 patients with RA, investigators were able to identify which factors might be predictive of an increased risk for serious infections in patients treated with TNF inhibitors (specifically age, corticosteroid use, visual analog scale pain, Health Assessment Questionnaire, tender joint count 28 joints, and comorbidities).[33] Thus, registries can provide additional information because of the greater patient diversity.[31] In truth, I think clinical trials and registries provide complementary types of information.

A recent study compared remission rates obtained from a clinical trial (Trial of Etanercept and Methotrexate With Radiographic Patient Outcomes [TEMPO]; N=682) vs those from an observational registry (Rheumatoid Arthritis DMARD Intervention and Utilization Study [RADIUS II]; N=4341).[34] Both studies investigated patients treated with ETN (with or without MTX) and found comparable rates of remission; however, remission was attained more rapidly in the clinical trial, possibly because of differences in patient populations, patient compliance, or the sequencing of combination therapy initiation.[34] Similarly, another study compared cost-effectiveness of infliximab treatment in patients, including those in a clinical trial (ATTRACT), patients enrolled in a Swedish registry (Stockholm Anti-TNF-α Follow-up Registry [STURE]), and the subset of patient in the STURE registry who met the inclusion criteria for ATTRACT.[35] Efficacy data were obtained either during the duration of the trial (ATTRACT) or over the course of 10 years (for patients enrolled in the registry). There were comparable cost-effectiveness ratios across all 3 groups, although the assumptions made in the different approaches had a large effect on the effectiveness data.[35] Comparing findings across registries can also provide information about differing treatment approaches. Zufferey found that biologics are prescribed at lower level of disease activity and after fewer prior DMARD failures in Switzerland than in other countries, which correlated with overall lower absolute levels of disease activity as well as better patient outcomes after 1 year of treatment.[36]

Medscape: Do you have any concluding remarks?

Dr Kavanaugh: We continue to refine our recommended treatment strategies for patients across all stages of RA. MTX remains an anchor drug: it can be used alone or in combination with many other agents. There is emerging evidence supporting the use of early combination treatment with MTX and a TNF inhibitor to facilitate rapid clinical remission and afford an improved quality of life. We also are accumulating evidence that we might be able to sustain remission, even among patients who discontinue TNF inhibitor treatment. However, the optimal therapeutic regimens and strategies for remission induction and maintenance remain controversial, and we still do not have clear-cut guidelines regarding when, and in whom, we should initiate TNF inhibitors in DMARD-naive patients.

Table. Treatments for Rheumatoid Arthritis

Disease-modifying antirheumatic drugs (DMARDs)Hydroxychloroquine
Leflunomide
Methotrexate
Minocycline
Sulfasalazine
Cyclosporine A
When appropriate, combination DMARD therapy with 2 or 3 DMARDs
Tofacitinib (Janus kinase inhibitor)
Non-tumor necrosis factor (TNF)-inhibitor biologicsAbatacept
Rituximab
Tocilizumab
Anakinra
TNF-inhibitor biologicsAdalimumab
Etanercept
Infliximab
Certolizumab pegol
Golimumab
From Singh JA, et al.[2]

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