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New Targets for Optimal Disease Control in Rheumatoid Arthritis

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

61st Annual Meeting of the Canadian Rheumatology Association and the 34th Mexican Congress of Rheumatology

Acapulco, Mexico / February 17-21, 2006

As discussed by Dr. Janet Pope, Professor of Medicine, University of Western Ontario, London, the percentage of patients with rheumatoid arthritis (RA) who achieve remission can vary considerably, depending on the definition of the instrument used. In one long-term follow-up of 161 patients with RA, for example, only 12% met the American College of Rheumatology (ACR) remission criteria of ACR70. Target numbers are also achieved only about 30% of the time, even in trials where rheumatologists have agreed to treat to a target number.

ACR responses in general appear to be superior when patients are treated with combination therapy such as the disease-modifying antirheumatic drug (DMARD) methotrexate (MTX) and the anti-tumour necrosis factor (TNF) agent etanercept. In TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes), 43% of patients randomized to the combination achieved an ACR70 response rate compared with only 19% and 24% in the MTX and etanercept monotherapy groups, respectively. Although these findings are an indication that anti-TNF agents work well in RA, they also underscore the fact that not all patients receiving optimal anti-TNF plus MTX therapy do well.

This perspective was reinforced by results from a telephone survey involving 500 participants with RA on a variety of medications. Among those who were using a biologic agent, 75% still reported experiencing daily stiffness, 71% had daily pain and 67% had daily fatigue. “Even patients who are doing well have a lot of symptoms,” Dr. Pope observed. Results from several RA databases, including the nationwide Danish DANBIO database, revealed that disease activity remains moderate to high in 70% of patients receiving anti-TNF therapy, with 30% of patients discontinuing anti-TNF therapy at one year. At two years, approximately two-thirds of patients registered in a Swedish database were still on biologic therapy, with discontinuation rates being similar for infliximab and adalimumab and somewhat lower for etanercept. In her own survey, Dr. Pope and colleagues found similar rates of treatment survival, at 70% at one year with an average of about 50% improvement in swollen joints.

“Most commonly, patients discontinue TNF inhibitors because of loss of efficacy,” Dr. Pope noted, although if a patient achieves a good primary response to the first anti-TNF agent, physicians may consider switching to a second agent. Dr. Pope also noted that in practice, switching can sometimes be a “waste of time” and that if a patient is a non-TNF responder to first-line anti-TNF therapy, it is unlikely that they will do well if switched to another agent in the same class. Other strategies which may be considered in TNF non-responders would be to add a DMARD, increase the dose of some biologics or change to a different class of biologics.

“Not all patients will have [either] a primary or a sustained long-term response to biologics such as anti-TNFs,” Dr. Pope concluded, “and there is a large unmet need for patients to have alternative treatment strategies in order to achieve the best possible disease control.”

The Role of B-cells in RA

As discussed by Dr. Boulos Haraoui, Clinical Associate Professor of Medicine, Université de Montréal, Quebec, RA is a very heterogenous disease in that different cells and cytokines drive the destructive processes in the disease. “If a patient is given an anti-TNF agent, other pathways that lead to joint destruction could be amplified or are still active, perpetuating joint destruction.” It has been demonstrated that interleukin-6 (IL-6) and, to a lesser extent, IL-1, are key drivers of joint damage. “Thus,” he noted, “we need a multitude of agents targeting different specific factors [driving the disease] and the more we have in terms of new agents, especially biological agents targeting specific cells, the more we will improve the management of RA and hopefully achieve complete remission and cure of the disease.”

One promising novel approach is to target the B-cell with anti-CD20 monoclonal antibodies (MAbs). As Dr. Haraoui discussed, it was previously believed the B-cell simply produced rheumatoid factor (RF). New research now suggests that the B-cell plays a much larger role in the pathogenesis of RA. For example, it is known that the B-cell secretes pro-inflammatory cytokines, including TNF, and that these cytokines in turn activate macrophages, which eventually promote both inflammation and joint destruction.

B-cells can also present antigens to the T-cell and they play an essential role in T-cell activation in the synovium. B-cells also produce autoantibodies and therefore the self-perpetuation of autoimmunity, Dr. Haraoui explained. He added that the B-cell matures from the original stem cell on up through to the mature plasma cell, but as the target CD20 antigen is expressed only on a subset of B-cells, “[anti-CD20 MAb] spares stem cells and it spares the plasma cells which are the cells that fight infection,” Dr. Haraoui told delegates.

The MAb destroys B-cells through different mechanisms, including complement-mediated B-cell lysis and cell-mediated cytotoxicity via macrophages and natural kill cells as well as through apoptosis, Dr. Haraoui noted. It also targets the T-cell by blocking antigen-presenting cells and the activation of T-cells, he added.

Other biologics that work through different mechanisms have also made a significant contribution to the management of RA. As several speakers discussed, IL-6 is not thought to play a role in the pathogenesis of RA, but it does activate osteoclasts that can lead to bone erosions and joint destruction. It can also activate B-cells, suggesting that it likely plays a role in the ongoing inflammatory process as well. The biologic abatacept was studied in the AIM (Abatacept in Inadequate Responders to MTX) trial, which was carried out in patients who had not achieved an adequate response to MTX. Tocilizumab (MRA), a new MAb that targets IL-6, has also been tested in patients with active RA who had not achieved a complete response to MTX.

The Role of Autoantibodies

A deeper understanding of the pathogenesis of early rheumatoid synovitis may well promote a different treatment paradigm in the management of RA, where specific strategies may be able to shut down persistence and even disease onset when strategically introduced. As discussed by several presenters, including Dr. Henri Ménard, Professor of Medicine, McGill University, Montreal, autoantibodies to peptidyl citrulline epitopes are both sensitive and specific to RA.

Even though several tests that detect autoantibodies against citrullinated peptides (anti-CCP) have failed in “the real world,” many patients test positive for the presence of these autoantibodies well in advance of clinical disease. Indeed, Dr. Javier Cabiedes, Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico, and colleagues reported here that the presence of anti-CPP autoantibodies correlated with higher disease activity both clinically and serologically as well as with a greater number of criteria for ACR, as did the presence of RF IgA, in a cohort of early RA patients. Citrullinated antigens have been found in synovial fluid, but intra-articular production of autoantibodies to citrullinated proteins occurs only in RA. Interestingly, Dr. Ménard and colleagues have recently shown that MTX decreases the overall autoantibody response to citrullinated antigens, which is probably why MTX is such a pivotal treatment in the treatment of RA. The question as to whether these autoantibodies are only a marker for RA or actually contribute to inflammation is an important one, for which there is no clear answer.

As discussed by Dr. Hani El-Gabalawy, Professor of Medicine and Immunology, University of Manitoba, Winnipeg, experimental work in animal models suggests that autoantibodies directed towards another protein, glucose-6-phosphate isomerase (G6PI) can precipitate a severe rheumatoid-like destructive arthritis. Interestingly, this arthritis can be induced in mice of many different genetic backgrounds simply by transferring serum containing autoantibodies to the G6PI protein. “These data confirm that autoantibodies directed against ubiquitous antigens, such as anti-G6PI, which is an enzyme found in all cells, can directly precipitate a destructive inflammatory arthritis, as long as the capacity to develop inflammation is intact,” Dr. El-Gabalawy explained in an interview. Nevertheless, extrapolation of these animal data to the human situation remains difficult.

Although some RA patients do have anti-G6PI autoantibodies in their blood and joint fluid, the presence of these autoantibodies is not specific for RA and is seen in several other forms of arthritis. In contrast, human RA is now known to be specifically associated with anti-citrulline autoantibodies, yet precipitating destructive arthritis with anti-citrulline autoantibodies has not been easily achieved in animal models. “My bias is that the initial anti-citrulline responses that precede clinical disease onset in RA patients are generated by a breakdown in tolerance to citrullinated antigens outside of the joints. The initial events that precipitate joint inflammation are non-specific and likely not mediated by these autoantibodies,” Dr. El-Gabalawy stated.

Once the joints become inflamed, new citrullinated antigens are exposed in the joint. Because of the previous breakdown in tolerance to citrullinated antigens, “immune responses to the synovial antigens are established and then become progressively amplified,” Dr. El-Gabalawy added. “In order to get amplification of anti-citrulline responses in the joint, you have to have a process of antigen presentation.”

Experiments have shown that the B-cell is critically important in the establishment of secondary lymphoid structures in the synovium, where the B-cells themselves become antigen-presenting cells and there is recognition of citrullinated antigens by T- and B-cells in the synovium. Not all patients with RA develop these secondary lymphoid structures in the synovium, Dr. El-Gabalawy noted. Yet for the subset of patients who do have the propensity to develop these lymphoid structures, “these are the patients who would be extremely well suited to early B-cell depletion, because if you can prevent the formation of these secondary lymphoid organs, you can basically cut off a very important persistence amplification pathway that will perpetuate this disease,” he noted, a strategy which he would consider “secondary prevention.”

If patients at high risk to develop RA could be identified by the presence of autoantibodies, among other genetic features, a strategy that helps recapture tolerance so they no longer respond to citrullinated antigens could abort the whole disease process before it even starts, Dr. El-Gabalawy concluded.

Questions and Answers

The following question-and-answer section was conducted during an interview with Dr. Boulos Haraoui, Clinical Associate Professor of Medicine, Université de Montréal, Quebec.

Q: Are there any strategies we can use to prevent tachyphylaxis from happening to the biologics as it does with the DMARDs and some of the other agents?

A: We are still learning about these agents and we are experiencing tachyphylaxis with infliximab, for example. Yet we also know that combining infliximab with DMARDs reduces the development of antibodies to infliximab and we also know that these antibodies are very specific to the molecule and they do not interact with rituximab, so switching patients from one agent to another will not compromise response if they have developed antibodies to another specific molecule.

Q: Should treating physicians consider switching patients to another class of agent if they fail anti-TNF therapy or should they consider switching to another anti-TNF agent?

A: It depends on the reason for the failure. If it is a primary anti-TNF failure, meaning the patient never responded from the start to an anti-TNF agent, then I think we need to switch to another drug category. If the failure is secondary or if the failure is due to toxicity, I think there is still room to use a second anti-TNF agent, as sometimes you do get a response to the second agent. But as we gain more experience with the newer agents, I think we could now switch to other biologics.

Q: Is there an opportunity to discontinue the biologic in patients who achieve a good response to combination therapy?

A: In the BeST (Treatment Strategies in Rheumatoid Arthritis) trial, where patients were getting infliximab plus MTX, 50% to 60% of patients who stopped their medication were still in a state of low disease activity after one year while still taking MTX. So probably we should be starting patients early on these agents to induce clinical remission and then they can take MTX afterwards and maintain low disease activity. In the long run, the early use [of the biologics] to get the disease under control, and then the use of low-cost treatment like MTX, will be cost-saving.

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