Advances in the Treatment of Rheumatoid Arthritis

Early Diagnosis and Treatment

The key to improving RA outcomes is early diagnosis and treatment, but this goal is frequently not achieved, reflecting patient, provider, and system issues. While RA is a common disease in the population, osteoarthritis (OA) is far more frequent and is the usual disease to which the term arthritis is used. Patients developing joint symptoms from RA often believe that they are experiencing the expected symptomatology that occurs with OA and aging. Patients may self-medicate, and time frequently passes before they seek medical attention. At that point, the disease may have progressed to the stage of damage. Education directed at the public is therefore essential to convey the messages that arthritis occurs in different forms and that joint pain is not an inevitable consequence of life.

Correspondingly, professional education is also important. Unfortunately, education for health care providers frequently lacks adequate instruction on musculoskeletal disease in general. When confronted by a patient with persistent joint pain and swelling, primary care providers may themselves not recognize the tell-tale evidence of RA. Furthermore, many patients with RA, depending on the pattern of joint involvement, may seek help from health care providers such as physical therapists to deal with a particularly painful or swollen knee, for example. Education on RA and related forms of inflammatory arthritis, as well as musculoskeletal disease in general, should therefore be increased, requiring funding to support teaching activities for health professionals.

At present there is a severe shortage of rheumatologists, physicians with specialized training in RA [8, 9]. This shortage is likely worldwide, and even in locations where there are rheumatologists, access may be limited due to a variety of factors (eg, significant delays in obtaining a referral). The solution to this problem is the development of better systems for patient triage and the creation of early arthritis clinics. In Europe, early arthritis clinics have been in operation for many years because of the increased access to specialty care inherent in their health care systems. Not surprisingly, European investigators have been in the forefront of research on the diagnosis and treatment of early RA and the development of early aggressive therapy and T to T.

Treat to Target

Early aggressive therapy with T to T approaches is designed to reduce inflammation, prevent damage, and alter the course of disease to limit late complications. As shown in many clinical studies, numerous agents alone or in combination can achieve this goal. Indeed, there are likely too many possible approaches to obtain hard evidence as to whether there is a preferred way. In general, an agent to rapidly reduce inflammation is an important element in early aggressive therapy and provides a foundation for other DMARDs to act [10, 11], with methotrexate as the anchor drug for most patients. Glucocorticoids at high doses are frequently used in this setting, although these agents carry significant toxicity and often are not well tolerated by patients, especially those with coexistent illness such as diabetes or hypertension.

Another approach to early aggressive therapy involves the use of biologic therapy, specifically tumor necrosis factor (TNF) blockers, in association with methotrexate. Given the pleiotropic actions of TNF, blocking this cytokine has many immunological effects, including a prompt reduction in inflammation marked by almost instantaneous pain relief and increased patient energy and well-being. TNF blockers also have powerful DMARD actions and could be considered for monotherapy, although in general they are used in association with methotrexate. The major difference between glucocorticoids in combination with methotrexate and therapy with a TNF blocker and methotrexate is cost [12]. TNF blockers are much more expensive and therefore payers try to limit their use to patients whose disease cannot otherwise be controlled.

Early aggressive therapy is therefore a junction point in RA treatment where cost considerations become very real. While biologic therapies are effective, they are expensive. The alternative approach of combination therapy with conventional DMARDs, such as hydroxychloroquine and sulfasalazine together with methotrexate (so-called “triple therapy”) and the use of glucocorticoids as bridge therapy, is also effective [12]. It is much less expensive, but it involves several agents and the inclusion of glucocorticoids and their associated side effects.

Many rheumatologists believe that initial therapy with a TNF blocker along with methotrexate represents one of the best current approaches to RA therapy. The side effect profile is also favorable. Nevertheless, cost considerations limit the use of this combination. The compromise is a more gradualist approach in which patients are treated with methotrexate first for a period of time (usually 3 months). For those patients who have not achieved a remission or low disease activity, an additional agent or agents, including a biologic, is added, with payers making judgments on the sequencing of agents or requesting justification for use of a biologic, as opposed to a less expensive combination.

This approach adds time and delay and incurs costs in communication and justification between a provider and payer; it also entails an administrative staff to navigate the system where there are multiple payers. As will be discussed later, the availability of biosimilars may change this situation and simplify the application of early aggressive therapy.

DMARD Withdrawal and Discontinuation

Fortunately, the treatment of RA with therapy has advanced to the point where many patients can achieve remission or a state of low disease activity. In the face of such attenuated and quiescent disease, patients and providers may both ask whether continuation of aggressive therapy is still necessary, or whether reduction in therapy is possible. This is a new situation, and data on the advisability of modifying DMARD therapy are just becoming available. These studies, which involve elimination of therapy or dose reduction, suggest that, at least for some patients, modification of the intensity of DMARD therapy is possible. While some patients may flare if a biological agent is eliminated, at least some may maintain their remission [13-15].

The elimination of an expensive agent and the obvious cost saving is an attractive approach for payers and pharmacy managers who wish to constrain expenditures. The future will undoubtedly see many studies to address this issue, and important questions will be asked, including: Do aggressive approaches differ in the likelihood of inducing remissions that can be maintained with the reduction or withdrawal of DMARDs? Do existing clinical measures give an accurate picture of ongoing inflammation or do they fail to detect silent disease that will continue to cause damage and disability? Does elimination or reduction of DMARDs affect the occurrence of later complications such as cardiovascular disease [16]? Data on these questions are needed for system-wide planning, resource allocation, and determination of best practices.

Biosimilars

The current considerations of the cost of care reflect current pricing. Although the field is filled with agents displaying similar levels of efficacy (including 5 TNF blockers), competition has not yet significantly affected drug pricing. The advent of biosimilars for biologics may alter this equation. Biosimilars are analogous to generics for small molecule drugs, although the technology for producing a protein and synthetic small molecule are sufficiently different that an alternative terminology is appropriate. A biosimilar shares the protein sequence with the originator product, but the conditions of production and purification may introduce some differences. These products are thus similar, with the extent of identity more difficult to assess [17, 18].

Price competition will likely occur between the originators and the biosimilars, rather than between the originator products. Nevertheless, the cost savings can be large, although the magnitude will depend on the health care system and the nature of the price negotiation. For rheumatologists, an important question concerns the reallocation of money that will be saved by any switch to a biosimilar. Will these savings be used to allow treatment of more patients with RA with biologics? Will they be used to support the therapy of patients with other diseases? Will they be used to simply reduce costs?