Refining Treatment Strategies in Rheumatoid Arthritis

Paul-Peter Tak, MD, PhD; Andrea Rubbert-Roth, MD, PhD; Ernest Choy, MD Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disease targeting the synovial membrane, cartilage, and bone. As a systemic disease, RA can affect organs and areas of the body other than the joints, such as lungs, pericardium, pleura, sclera, and subcutaneous tissue. If RA is not treated early and adequately, progressive deformity can lead to loss of quality of life and reduce average life expectancy by about a decade, causing significant economic impact.

The ultimate goals in treating RA are to prevent or control joint damage, prevent loss of function, and decrease pain. Pharmacologic therapy for RA is designed to alleviate pain and inflammation, and to intercept the destructive processes associated with immune-mediated inflammatory diseases. Better understanding of current conventional and biologic therapies, as well as emerging treatment strategies for managing both joint and systemic manifestations of RA will aid in guiding treatment decisions and improve patient care.

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Let us now discuss classic treatment and specific requirements. When we look at this algorithm, I would like to highlight 2 points. It is critical to start treatment as early as possible. Early, aggressive intervention is very important. Second, we want to treat-to-target. We need to measure disease activity in a systematic way; the goal is not to have relative improvement, but to achieve a state of low disease activity or, preferably, remission. We do this by using conventional disease-modifying antirheumatic drugs (DMARDs) as early as possible. When there is still active disease, or when the patient does not tolerate conventional DMARDs, then we switch to biological treatment.

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Specific requirements, based on disease status, may help to guide treatment decisions. As we will see, RA has many systemic features, not limited to joints, including anemia, fatigue, and cardiac manifestations. There may also be patients who require monotherapy. The question is: who? This illustration shows you that RA manifests itself in the joints, leading to inflammation in the synovium, progressive joint destruction and disability. However, it may also have effects on the bone marrow, resulting in anemia and changes in platelets and leukocytes. These manifestations may be very important for the patient and may guide our decisions in choosing the correct treatment.

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When is monotherapy with biologics potentially indicated? In patients previously treated with conventional DMARDs who discontinued therapy due to side effects or lack of efficacy, and in patients with contraindications to conventional DMARDs, such as renal failure or hepatic disorders.

Let us now address customizing treatment strategies for disease heterogeneity. Ernest, would you tell us more about this?

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Ernest Choy, MD: In ideal circumstances, we would have a blood test to tell us the optimal treatment for a patient. In the absence of that ideal scenario, we can try to select patients for specific treatment based on our understanding of the biology, and how different cytokines lead to systemic manifestations of RA. This is illustrated by the improvement in patients treated with different biologic agents. In addition, we will look at some of the most important systemic manifestations of RA, such as cardiac manifestations, and how systemic inflammation contributes to them.

Anemia is one of the most common systemic manifestations, occurring in one third to two thirds of patients with active RA. Although patients with severe anemia (hemoglobin of < 10 g/dL) are not common, many patients have mild anemia. In fact, in many of the clinical studies we have observed, an increase in hemoglobin level leads to improvement in physical function, which is independent of changes in disease activity.

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I will illustrate this with studies from a number of biologic agents. If we look at the course of anemia — we know cytokines are a potent stimulator of the acute phase response, particularly interleukin (IL)-6. When you stimulate hepatocytes with IL-6, they produce hepcidin. Hepcidin causes anemia by 2 mechanisms: it reduces iron absorption from the gut, but even more importantly, it stimulates macrophages to sequester iron. Together, these mechanisms deprive the bone marrow of the necessary iron to make hemoglobin.

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In the ARMADA [Anti-TNF Research Study Program of the Monoclonal Antibody Adalimumab] and STAR [Safety Trial of Adalimumab in Rheumatoid Arthritis] studies, treatment with adalimumab results in a 0.2- to 0.4-g/dL increase in hemoglobin concentration.

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A larger increase in hemoglobin level is associated with tocilizumab, as it is a direct inhibitor of IL-6. If you look at this pooled analysis of the OPTION [Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders] and TOWARD [Tocilizumab in Combination With Traditional DMARD Therapy] studies, you see about a 1-g/dL increase in hemoglobin concentration after treatment. In fact, in patients who are significantly anemic, the magnitude of improvement is much greater.

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Fatigue is another key complaint of patients with RA. About 40% of patients reported that fatigue causes them significant problems in performing daily activities, independent from pain. In fact, some patients complain that fatigue is an even bigger problem than pain. This is reflected by OMERACT [Outcome Measures in Rheumatoid Arthritis Clinical Trials] 2006, which stated that fatigue should be included in the core data set to be assessed in all randomized control trials. This shows how important fatigue is as an outcome, and that it affects the quality of life in patients with RA.

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In fact, one of the biggest impacts of biologic treatment is on the improvement of fatigue. We see it with tumor necrosis factor (TNF) inhibitors. This is fatigue change associated with adalimumab treatment in a randomized control trial. The increase in fatigue is much better in the active treatment group compared with placebo-treated patients.

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A similar magnitude of improvement is seen in the fatigue score of patients treated with the IL-6 inhibitor, tocilizumab, compared with placebo-treated patients. This includes patients who are biologic naive as well as patients who had previously failed TNF inhibitors.

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Cardiovascular events are also increased in patients with RA, contributing significantly to their mortality. In contrast to patients with ischemic heart disease, cardiovascular events in patients with RA are likely related to systemic inflammation. Even cardiologists now consider atherosclerotic disease as a chronic inflammatory disease within the blood vessel wall. Inflammation is a major component. For example, we know that C-reactive protein (CRP) level is a good predictor of future cardiovascular events, even in apparently healthy individuals. There is good evidence that suppressing inflammation can reduce cardiovascular risks. We have seen it with methotrexate. We have also seen it with TNF inhibitors, within the CORRONA [The Consortium of Rheumatology Researchers of North America, Inc. ] database. I think there is good reason to believe that potent inhibitors of inflammation, such as tocilizumab, which reduces CRP levels, may have an impact on cardiovascular events.

Dr. Tak: Andrea, do you have any comments to add?

Andrea Rubbert-Roth, MD, PhD: It is interesting to observe the new drugs that we are using. For instance, in Germany we did a phase 3b trial with tocilizumab, where the patients used a diary every day after the first infusion to mark on a scale how they felt about morning stiffness, fatigue and pain. We noticed, and heard from the patient, that sometimes systemic symptoms improved earlier than the apparent effect on the joints.[1] It is quite a new area of interest for us as rheumatologists. There may also be associations between pro-inflammatory cytokines and the neuroendocrine system that we also have to learn and truly appreciate.

Dr. Tak: Absolutely. Ernest, can you briefly tell us how you use this in your treatment algorithm?

Dr. Choy: Most clinicians will recognize that from the pre-biologic era, conventional DMARDs can reduce the number of tender swollen joints and erythrocyte sedimentation rate to some degree. However, the impact on fatigue is very, very small. Often patients with severe fatigue use the term “I am completely washed out; I cannot do anything because I am so tired.” In the modern biologic era, those are patients you would want to consider for early anti-cytokine therapy.

Dr. Tak: Absolutely. Thank you very much. Let us now focus on patients who require monotherapy. Andrea, can you tell us more about them?

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Dr. Rubbert-Roth: Monotherapy is quite an interesting concept because, for a couple of years, combination therapy was favored by a lot of rheumatologists as well as supported by data. However, newer data and data from the most recent meetings support the eventual use of biologics in monotherapy. We know from registries that about 30% of patients actually use biologics as a monotherapy, regardless of their approval status.[2] But, it is convenience and sometimes intolerance to conventional DMARDs that drive patients and physicians to this decision.

Looking at data from trials with TNF inhibitors, the ERA trial involved patients with early RA and compared the use of methotrexate in monotherapy to etanercept in monotherapy to the combination. In the TEMPO trial, the patients were not as early as in the ERA trial, but it also compared combination therapy to the 2 monotherapies. Another example is the PREMIER trial, which used adalimumab in patients with early, aggressive RA.

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What was very interesting to see, in the PREMIER trial, was the percentage of patients who achieved clinical remission after 1 year and 2 years. It is nice to see that adalimumab and methotrexate are synergistic. However, monotherapy with adalimumab and methotrexate are almost equally effective.

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From a clinical point of view and the effect on radiographic progression, adalimumab monotherapy seems to be more potent than methotrexate monotherapy, at least in this patient population. This patient population is composed of individuals who are at high risk for radiographic progression. These findings may not necessarily be identical in other patient populations.

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Golimumab, a newer compound, is a human anti-TNF antibody that is used once a month as a subcutaneous injection of 50 milligrams. The GO-BEFORE [Golimumab Before Employing Methotrexate as the First-line Option in the Treatment of Rheumatoid Arthritis of Early Onset] trial used golimumab in methotrexate-naive patients as a monotherapy compared to methotrexate and to the combination therapy. It is the same picture. The TNF inhibitor as a monotherapy is not better than methotrexate alone, but together there seems to be a synergistic effect.

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The same holds true for GO-FORWARD [Golimumab for Subjects With Active RA Despite MTX]. In this case, the ACR responses are depicted. It is an accepted paradigm that TNF inhibitors are most effective when combined with a DMARD, and this has been most extensively studied with methotrexate.

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Switching to another therapeutic principle, tocilizumab is a blocker of the IL-6 signaling pathway and has been studied primarily in Japan before the start of the global program. From Japan, the first results looked at clinical efficacy as well as the potential to inhibit radiographic progression. The SAMURAI [The Study of Active Controlled Monotherapy Used for Rheumatoid Arthritis, an IL-6 Inhibitor ] trial is an example where tocilizumab was used in monotherapy, resulting in a profound inhibition of radiographic progression.

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The AMBITION trial, a global clinical trial, was set up in patients who were either methotrexate naive or had not failed previous DMARD or anti-TNF therapy (i.e., started to take it but stopped for various reasons). This data clearly shows that, in the methotrexate-naive patient population, tocilizumab is superior to methotrexate. This was statistically significant.

It is indeed the situation that we face often in the clinic that, as you said, patients are normally started on methotrexate. There are a proportion of patients that are doing fine on methotrexate alone. However, when patients still have active disease despite being on methotrexate, it would be normal to add tocilizumab. The question that many patients have is: “Do I really have to continue with the methotrexate?” Apparently the patient feels that the medication is not helping. In fact, a lot of patients have subclinical nausea, vomiting, or headaches when taking methotrexate.

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New data from the ACT-RAY trial was presented at the 2011 European League Against Rheumatism (EULAR) meeting. This study was performed in patients who had an inadequate response to methotrexate. The patients were randomized to either having tocilizumab added to their methotrexate therapy, or they were switched to tocilizumab monotherapy. This nice result shows that the patient outcome after 24 weeks is almost identical. This is something we have to think about, as a new strategy in the future; whether we should eventually offer to decrease or even stop methotrexate in patients who are selected for tocilizumab therapy. This may be an effective option. It is a new concept in how we treat patients, getting away from this paradigm of combining everything with methotrexate.

Dr. Tak: Do you expect to see fewer side effects when using tocilizumab monotherapy compared to combination therapy with methotrexate?

Dr. Rubbert-Roth: Using the combination of tocilizumab and methotrexate we have been observing that there are patients who experience an increase in liver enzymes. What we did in the past, at our university, was to stop methotrexate knowing that the patient had previously failed on methotrexate. In the end we were not quite sure whether this approach was correct or if it might affect the outcome. The ACT-RAY trial gives us some confidence that this is the best way to do it for the patient. Analyzing safety data from ACT-RAY shows that the incidence of liver enzyme elevations is probably less with monotherapy.[3]

Dr. Tak: Ernest, do you have anything to add?

Dr. Choy: I completely agree with Andrea’s point. We are moving into a phase of using combination therapy. Clinicians are very confident about combination therapy and about using these agents. Randomized control trials do show that certain combinations are better than monotherapy. However, our patients do not like taking lots of medicine. If they had a choice, patients would want to take the least amount of medicine while maintaining the same degree of control. We may move to an era where we try to achieve very rapid disease control and gradually taper off the medicine, similar to oncologists. They induce remission, remove some medication and try to keep the patient stable.

Dr. Tak: I would like to focus on treatment optimization with currently available drugs. Let us focus on the long-term safety of treatment. Andrea, can you comment on this?

Dr. Rubbert-Roth: We just started to speak about what patients prefer. Another issue that patients are concerned with is potentially continuing methotrexate for a couple of years; the question of safety always comes up. In particular, with the newer drugs, it is important for physicians to look at registries for the presence of safety signals, and to be updated on the results from safety databanks. It is important to keep in mind that patients selected for modern clinical trials are usually not patients we would treat in daily practice. These are mostly patients without comorbidities or significant comedications; basically all of the patients are hepatitis B- and C-negative, and without any prior malignancies. It is a very selective patient population. For this reason, we need long-term safety databanks. However, we still need registries to get a better picture of how a drug is doing in real life.

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Another important aspect is immunogenicity of monoclonal antibodies. Some monoclonal antibodies are engineered with mouse particles, such as infliximab and rituximab, and others are fully human. But we know that even fully human antibodies may provoke an immunological response. There are some abstracts at EULAR 2011 showing that antibodies, such as infliximab, can interfere with drug efficacy. Patients develop antibodies to the drug. This will lead to lower drug serum levels, a reduced level of response, and possibly serious side effects during infusion. This is something to take into account and carefully monitor when deciding whether to switch patients to another therapeutic principle.

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We have been using biologics for more than 10 years. Speaking about long-term safety of biologics, we have learned it is important to watch out for serious infection. We should never start using a biologic while a patient has a serious infection. Opportunistic infections are also possible, and we are now pre-screening patients for the presence of latent tuberculosis. This is certainly something we should keep doing. Other opportunistic infections should be kept in mind, depending on which country the patient comes from or lives in, because there may be regional differences.

Ernest mentioned cardiovascular events already. In particular, we have to monitor lipid profiles. Malignancies are also something to keep in mind, because all of the trials have involved patients without prior malignancies. What do we do for patients who had breast cancer 5 years ago? There are a lot of issues to discuss. Also, recent data has shown that the use of glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk of gastrointestinal perforations in RA patients. This has been observed as well with TNF inhibitors, and maybe a bit more frequently with tocilizumab. This is likely telling us something about patient selection. For instance, if a patient has a history of diverticulitis, I would not decide to use tocilizumab as a first-line therapy. Similarly, I would not consider TNF inhibitors to be the best choice in a patient who has just cleared tuberculosis. I think the safety profiles help us in selecting patients.

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I would like to give a brief overview about the incidence of serious infections during treatment. Data from the British Registry shows that when using TNF inhibitors, the incidence of serious infections per 100 patient-years is expected to be in the range of five-point-something. Data from the rituximab and tocilizumab safety databanks show a similar range.

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We have 9 biologics on the market, which is quite a large number, and the Cochrane analysis compares serious adverse events and serious infections among the various biologics. The newer biologics, such as tocilizumab, are within the range observed for the other cytokine inhibitors.

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As for malignancies in RA patients, RA patients tend to have a higher risk of lymphoma and lung cancer, according to their disease activity. Based on numbers combined from various databases and registries, we calculate that about ten malignancies are to be expected per 1000 patient-years in patients treated with biologics. This is thought to be the same in patients whether they receive biologics or DMARDs.

Dr. Tak: Do you have anything to add, Ernest? Do you agree?

Dr. Choy: I agree with all those comments, they are very pertinent. Potentially, this has implications for how we develop future treatment strategies.

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Dr. Tak: So that brings us to future strategies using current treatments. We have discussed improved diagnosis and early treatment. It is important to come to an appropriate risk assessment, and we need to think in terms of personalized treatments now that we have different treatment options.

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The question is, how can we choose the optimal targeted therapy for a specific patient? There is still a lot of development needed, but it has become clear in recent years that we should not view RA as a single disease entity based on one specific pathogenetic mechanism. There are more and more data from clinical and molecular science indicating that RA should probably be viewed as a syndrome consisting of different pathogenetic subsets. There are patients who have a very pro-inflammatory gene profile in their synovial tissue, and others who have a pattern characterized by stromal cell activation. However, we cannot distinguish between these 2 subsets clinically; we call them RA.

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It is conceivable that some patients with a specific molecular signature are better candidates for treatment A, whereas others may be very good candidates for treatment B. In light of the increasing number of available biologic agents, it will be critical to understand their mechanisms of action, how these mechanisms are linked to RA disease pathogenesis, and their optimal use in a clinical setting.

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