Keywords

Introduction

Rheumatoid arthritis (RA) is a progressive, systemic inflammatory disease that targets synovial tissues. Left unchecked and untreated, RA can cause significant morbidity and accelerated mortality. RA is the most common inflammatory arthritis in adults, with a peak age of onset between 40 and 60 years of age. However, as remission is uncommon, it has become appreciated that the prevalence of RA increases at least through age 85. The prevalence of rheumatoid arthritis among persons 60 years of age and older has been estimated at around 2% [1]. In the general population of elderly persons, arthritic complaints are most frequently associated with osteoarthritis (OA), classically considered a degenerative and noninflammatory form of arthritis. However, various forms of inflammatory arthritis, including RA, gout, calcium pyrophosphate deposition disease (CPPD) or pseudogout, polymyalgia rheumatica (PMR), and even inflammatory forms of OA are commonly encountered as well. A major concern shared among various arthritic disorders is their potential to diminish elderly patients’ functional status, and therefore, their independence. Pain, stiffness, and even constitutional symptoms can contribute to immobility, weakness, and increased falls. These can in turn lead to decreased quality and even quantity of life.

Even though there has been progress in deciphering the cellular and molecular mechanism of RA, the etiology is still not fully defined. RA is characterized by synovial and vascular proliferation with the formation of pannus tissue [2]. The synovium thickens due to increased number of activated immune cells. These cells produce a host of inflammatory mediators, notably proinflammatory chemokines and cytokines that help drive synovial proliferation. The secretion of these cytokines as well as enzymes, such as matrix metalloproteinases (MMPs), can cause tissue destruction with damage to articular cartilage and adjacent bone–repetition above [3].

Clinical Features

Two clinical presentations of RA can be broadly defined in the elderly population [4]. The first, commonly known as elderly onset RA (EORA), refers to the de novo development of rheumatoid arthritis in persons older than an arbitrary age, typically 60 or 65 years. The second presentation of RA encountered in elderly patients is RA that develops before the age of 60 or 65 and that persists into older age; this is commonly known as younger onset RA or YORA. In the literature, there is some controversy about whether and how those with YORA might differ from those with EORA as regards disease characteristics, such as typical signs and symptoms of disease and key outcomes.

It has been suggested that EORA is commonly characterized by disabling morning stiffness and marked pain predominantly affecting the upper extremities. The physical examination may be particularly remarkable for pronounced synovitis of the shoulders and the wrists as well as the metacarpophalangeal (MCP) joints and proximal interphalangeal (PIP) joints, with marked limitation of motion and soft tissue swelling. Involvement of large joints, in particular shoulder joints, has been said to be a striking and characteristic feature of EORA [5, 6]. As compared to YORA patients, those with EORA have been reported to have a more acute onset and more highly elevated erythrocyte sedimentation rate (ESR) levels [7, 8]. Sex differences exist between the two types of RA. With YORA, women are three to four times more likely to be affected than are men; in EORA, there is a diminution of such a female predominance [9].

It is important to make note of several factors when considering differences between EORA and YORA. A particularly relevant one is disease duration, as that impacts many relevant disease characteristics in RA. Given that the peak age of onset of RA is between 40 and 60 years of age, a significant number of YORA patients have suffered disease activity for a considerable amount of time, from years to even decades. As a result, they are much more likely to have an advanced stage of the disease. Many have received therapy with multiple therapeutic agents, and some have undergone orthopedic surgical procedures. The physical examination of these patients may reveal varying degrees of both active polyarticular synovitis as well as the sequelae of joint damage, namely, deformities such as ulnar deviation of the hands along with swan-neck and/or Boutonniere deformities, flexion contractures of the elbows, and wrist subluxation. In addition, systemic manifestations, such as rheumatoid lung, vasculitic ulcers, peripheral neuropathy, and even secondary amyloidosis, all reflecting longstanding inflammatory disease, may occur more commonly among YORA than EORA. This can complicate the care of this population of RA patients.

Differential Diagnosis

The differential diagnosis of RA in the elderly may be particularly complicated since the sensitivity and specificity of rheumatologic laboratory tests may differ in older versus younger patients. For example, it is well established that the prevalence of auto-antibodies, including serum rheumatoid factor (RF) increases with advancing age. This affects the utility of RF for the diagnosis of RA in the older population [4, 9]. It has been suggested that anti-cyclic citrullinated antibodies that react with a common epitope identified by anti-filaggrin, anti-perinuclear, and anti-keratin antibodies, may have greater specificity in an older population [10].

The ESR and C-reactive protein (CRP) tend to be elevated in active inflammatory conditions and are often used in RA to help quantify the activity of rheumatoid synovitis. In addition, persistent elevations in these acute phase reactants are associated with a less favorable prognosis in RA patients. However, the ESR tends to increase nonspecifically in older persons. In some cases, elevations may relate to other comorbid conditions, such as infection, congestive heart failure, hypercholesterolemia, or malignancy. Even among healthy persons, “normal” values for ESR increase with advancing age.

Perhaps of greatest relevance to the accurate diagnosis of RA among older persons is the presence of various other articular conditions that may have signs and symptoms very similar to RA. Included herein are PMR and CPPD, which has also been referred to as “pseudo-RA”; gouty arthritis, and OA including inflammatory forms of OA. Several of these, such as OA and gout, are more prevalent among the elderly than is RA. The rigor with which these other conditions are excluded certainly affects the ability to accurately assess the medical literature as it pertains to EORA. For example, if it is highly likely that some published series of EORA included patients who did not have RA, but rather had one of these other arthritides. This has important implications as regards “characteristic” presentations of EORA, including its expected outcome.

Radiographic evaluation may not always be helpful as a diagnostic test in older patients suspected of having EORA. This is particularly true among those with a recent onset of symptoms because in the early stages of the disease only soft tissue swelling and periarticular osteopenia are present. Finding radiographic characteristics of RA, such as uniform joint space loss, marginal erosions, and intra-articular deformities may be seen in more established disease.

Potential prognostic factors have not been studied as extensively in EORA as they have for RA in general. Interestingly, the overall outcome for patients with EORA has been reported to be both better [6, 10] and worse [5] than YORA. This disparity may well relate to confounders in the published literature, such as diagnostic inaccuracy, failure to control for disease duration, and the presence of more comorbid medical conditions among older persons. A frequently cited feature of EORA, acute onset of symptoms, has also been associated with a worse [11], equal [12], and a better [13] prognosis as compared to EORA with a more insidious onset. In several reports, EORA patients who are seropositive for RF have been demonstrated to have either similar or worse prognosis when compared with younger seropositive RA patients [8, 14]. However, more aggressive disease was seen in RA patients not stratified for age that have high positive titers of RF, radiographic evidence of bony erosions, arthritis of more than 20 joints, rheumatoid nodules, HLA-DR4 allele, and elevated acute phase reactants [15]. The pro-inflammatory cytokine pattern could also play a role in the prognosis of EORA. It has been suggested that the lower levels of serum TNF-α might play a protective role in elderly RA patients [16].

Aging Factors

Several factors should be considered while interpreting the results in elderly. Changes in the immune system associated with aging, such as T cell functional characteristics, defects in apoptosis, decreased specific antibody responses and antigen processing, cytokine imbalances, and thymic involution, may all play a role in the way a disease is manifested in the elderly [17]. Disease duration may contribute to a poor prognosis in the elderly by having a negative impact on the functional status of elderly patients, for example YORA as compared to EORA. Comorbidity is another factor that contributes to the apparent worse prognosis among older patients. Intercurrent illnesses and their therapies might cause patients to be less tolerant of the inflammation and other burdens caused by RA itself. Hormonal changes, especially those associated with estrogen, progesterone, and androgen levels in the older population might also affect RA in the elderly [17].

Treatment

The primary goals of treatment for RA – to alleviate pain, prevent or limit joint damage, optimize the quality of life, avoid complications of therapy, and improve or preserve function – are similar in both EORA and YORA. However, the efficacy and toxicity of drugs commonly used in RA may have some differences between the populations. Thus, the optimal therapeutic management of RA in elderly patients is complicated by a greater chance for diagnostic uncertainty, increasing the presence of comorbid conditions that affect drug metabolism or toxicity, and changes in pharmacokinetics that occur with normal aging. These all may lead to an increased frequency and/or severity of adverse drug events in older persons as compared with younger populations [4, 9].

In recent years, many new agents for the treatment of RA have been investigated, and a considerable number are under study at present. It is important to note that the elderly population is generally underrepresented in clinical trials despite the fact that the prevalence of RA is high and increasing in this age group. One of the most notable trends in the past decade regarding the treatment of RA has been the growing consensus that the institution of an aggressive approach early in the course of the disease may be the best way to prevent irreversible joint damage and to spare patients years of pain and discomfort. Current strategies include early aggressive treatment with one or more disease modifying anti-rheumatic drugs (DMARDs), along with symptomatic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose prednisone. In addition, biologic agents, which had been reserved for RA patients with refractory disease, are being used much earlier in the disease course. Studies proving the value of these approaches have not generally recruited large numbers of older persons. There are probably several factors that contribute to this, including the greater prevalence of comorbid disease among older persons. However, there is some information concerning the treatment of older RA patients with all of the therapies available.

NSAIDs can reduce pain and, at higher doses, inflammation for many RA patients; however, they do not slow joint damage [18]. A major consideration with the use of NSAIDs in the elderly is the increased risk of adverse effects. Important toxicities that are of particular concern because they may occur more commonly and/or be associated with worse sequelae in the elderly include: upper gastrointestinal bleeding, renal insufficiency, worsening of hypertension, worsening of congestive heart failure, and central nervous system dysfunction [19]. The most appropriate methods for routine monitoring of toxicity from NSAIDs remains controversial, and the side effects can be unpredictable. Cyclooxygenase-2 (COX-2) specific inhibitors (COXIBs) have been proven to be safer compared with nonselective NSAIDs from the gastrointestinal standpoint and have comparable efficacy to traditional NSAIDs [19]. However, coxibs’ impact on renal function and blood pressure is comparable to nonselective NSAIDs and careful monitoring of blood pressure is warranted after initiation of these agents as it is for any NSAID [20, 21]. There is some recent data suggesting that certain coxibs especially at higher doses may increase the rate of thrombotic and cardiovascular events [22] although this issue remains controversial. Coxib and NSAID usage is advised to be initiated with the lowest recommended dose especially in low weight subjects because higher plasma may be detected in elderly patients [23].

Oral glucocorticoids at lower doses, which are often defined at less than 7.5 or 10 mg prednisone equivalent per day, are often used to help control inflammation, and thereby improve symptoms, such as pain and stiffness. They have recently been shown to potentially slow progression of joint damage as assessed by serial radiographic analysis of the joints [18]. Some patients may benefit from the use of low-dose oral steroids when there is a flare of RA disease activity and while other therapies are being initiated. In fact, in the past, the use of low-dose prednisone was advocated as the second-line therapy in elderly patients with RA based on steroids rapid mode of action and the sense that elderly patients may functionally deteriorate faster than younger population [24, 25]. A moderate to excellent improvement with prednisone therapy was reported in 80 of 91 patients with EORA [25]. However, in the long run, steroids do not seem to have as prolonged or notable an effect on functional status as is seen with other types of therapy. More importantly, steroid therapy can be hazardous especially in elderly patients since it poses an increased risk for adverse effects, including osteoporosis, infection, glucose intolerance, gastrointestinal erosive disease, and hypertension. There is data that suggests that with the long-term use of low-dose prednisone, the risk of osteoporosis may outweigh the clinical benefit [26]. Therefore, strategies, such as the use of bone protective agents and monitoring of toxicity, are warranted with chronic usage of steroids.

DMARD therapy can change the course of RA, resulting in sustained improvement in physical function, decreased inflammatory synovitis, and potential slowing or prevention of structural joint damage in a subset of treated patients. Methotrexate (MTX) is the most commonly used DMARD for the treatment of RA, in patients of all ages. With a solid efficacy record and well-defined toxicity profile, it is the first DMARD used in most RA patients. Among elderly RA patients, who may have preexisting renal dysfunction, attention to renal function is required, and the doses used may need to be modified. There is indeed evidence that clinicians are more cautious with the use of MTX among older persons, and do use a lower dose, despite the same level of disease activity, than they use for younger RA patients [27]. Hydroxychloroquine (HCQ) and sulfasalazine (SSZ) are used most commonly in patients with milder or more slowly progressing disease as they are in general considered less efficacious than MTX. Leflunomide is approved for use as monotherapy or in combination with MTX, although the latter approach is not commonly used among older persons due to concerns for toxicity [28]. Other combinations that are sometimes used in patients with insignificant clinical improvement on single therapy include MTX  +  HCQ  +  SSZ or placebo [28]. Cyclosporin and azathioprine are reserved for refractory patients who have failed other agents. Close follow-up and regular monitoring are typically required for patients on DMARDs. Some studies, including patients older than 65 years of age, have found no significant effect of age on termination of DMARD treatment [29, 30]. In addition, a tendency toward less efficacy and toxicity of DMARDs has been reported in older compared to younger patients [29, 30]. However, in these studies prolonged disease duration might be the factor for early discontinuation of therapy rather than age, since it is well documented that many patients fail to remain long term on any given DMARD.

A better understanding of the immunopathogenesis of autoimmune diseases and advancing developments in biopharmaceutical technology has led to the introduction of several biologic therapeutic agents. In RA, the introduction of biologic agents has dramatically changed the treatment paradigm. Biologic agents are designed to specifically target and inhibit various components of the immune system and inflammatory response that are considered central to the pathogenesis of RA. To date, the greatest success has been achieved with inhibitors of the pro-inflammatory cytokine TNF. Currently, there are five anti-TNF agents available for clinical use: infliximab, a chimeric anti-TNF-α monoclonal antibody (mAb); etanercept, a soluble dimeric TNF-receptor/IgG-Fc piece fusion construct; adalimumab, a human anti-TNF-α mAb; certolizumab pegol, the Fab fragment of a humanized anti-TNF-α mAb linked with polyethylene glycol residues, and golimumab, a human anti-TNF-α mAb. Early studies were conducted in patients with chronic refractory RA, but more recently patients with early RA have also been studied. Treatment with the TNF inhibitors has resulted in rapid and sustained improvement in signs and symptoms of disease. In addition, functional status has been markedly improved with all three agents [31–33]. Perhaps most notably, joint damage as measured by X-ray progression, appeared to be inhibited by the use of these drugs [34–36]. The optimal treatment paradigm for RA appears to be a TNF-inhibitor in conjunction with MTX, as there appears to be a synergy with the combination for all key clinical outcomes.

While studies of TNF inhibitors specifically in elderly RA patients have not been conducted, some older persons have been included in the clinical trials. In a retrospective analysis of four double-blind studies of etanercept, it was noted that 197 of the total of 1,128 patients were older than 65 years. Treatment appeared to be as effective in older persons as it was in younger patients, and tolerability was also comparable [37]. In fact, older patients reported a lower rate of injection site reactions, headache and rash compared to younger patients. TNF inhibitors clearly represent a major advance in the treatment of severe inflammatory arthritis. However, a greater frequency of conditions generally considered to be contraindications to TNF inhibitor use (e.g., congestive heart failure, chronic infection) that are found in the older population may limit their usage [37]. Indeed, analysis of use of TNF inhibitors in clinical practice showed that despite comparable disease activity and comparable tolerability, rheumatologists tended to use TNF inhibitors less frequently for older persons. In that study, EORA patients were matched with YORA patients based on their disease duration and compared in order to assess the types of treatment measures used in the two groups. It was shown that EORA patients received biologic therapy and combination DMARD therapy less frequently than YORA patients, despite identical disease duration and comparable disease severity and activity [27]. This suggests that there may be a need to use more aggressive therapeutic regimens in the geriatric population.

In addition to TNF inhibitors, other biologic agents have been approved for use in RA. Anakinra is an interleukin-1 (IL-1) receptor antagonist. It tends to be used in patients who are refractory to other treatments and either did not have a good response to or had contraindications to the use of TNF blockers. The overall magnitude of reductions in clinical symptoms and signs were relatively modest when compared to those reported in TNF-α blocking agents, and the drug is not frequently used [31, 32]. Anakinra should not be used in combination with TNF blockers as this results in greater toxicity without additional benefit. Injection site reactions are the most frequently reported adverse event with anakinra [38]. Abatacept (CTLA4-Ig) is a fusion protein designed to modulate the T cell co-stimulatory signal mediated through the CD28-CD80/86 pathway. It inhibits full activation of T cells. Clinical trials have provided evidence for the efficacy of abatacept in patients with active RA, despite prior treatment with MTX or anti-TNF therapies [39, 40]. Rituximab is a chimeric anti-CD20 mAb that has been approved for the treatment of B-cell lymphoma since 1997. Rituximab causes selective and rapid transient depletion of the CD20+ B cell population. It was subsequently shown to be effective in RA patients, including those who fail to respond to TNF inhibitor therapy [41, 42]. Neither abatacept nor rituximab have been studied specifically among elderly RA patients.

Summary

Changes in immune activity, physiological deterioration, and other factors associated with aging affect the pathological process of RA and account for the differences in characteristics between EORA and YORA. These changes also influence the prescription and efficacy of medications in the elderly. Since the prevalence of RA is increasing in the elderly population, it is important to further study various aspects of EORA and also include the elderly in more clinical trials. Identification of an optimal EORA management plan could significantly improve the quality of life of older patients.