Targeting Low Disease Activity in Elderly-Onset Rheumatoid Arthritis: Current and Future Roles of Biological Disease-Modifying Antirheumatic Drugs

Elderly RA is categorized into two clinical subsets; EORA and younger-onset elderly RA [10]. Onset after 60 years of age is mainly adopted as the classical definition of EORA in the literature. This definition of EORA has been used throughout this review unless otherwise specified, although we recognize that elderly individuals are generally healthier in the current aging society than ever and the definition of elderly-onset should be validated or modified in future.

Previous epidemiological studies showed a declining trend in the incidence rates of RA in the period 1955–1994 [11]. However, the incidence rate of EORA (age >64 years) increased from 1980 to 2000 [12]. Recent epidemiological studies in Minnesota showed an increasing trend in the incidence rates of RA from 1995 to 2007 in women of each age category [13]. The incidence rates of RA in the 1995–2007 period were highest in individuals aged 65–74 years and decreased over the age of 75 years. The cumulative risk of RA rose sharply around 60 years of age [14]. A recent large RA registry in the United States showed that approximately one-fourth of the enrolled patients were diagnosed with EORA after the age of 60 years [15, 16]. In a Swiss prospective observational cohort for early RA and undifferentiated arthritis (disease duration after the first symptom ≤1 year), the age at disease onset had a Gaussian distribution with a single peak between 50 and 60 years and was ≥60 years in 38.2 % of the 592 patients [17]. Because life expectancy has increased in the general population and people aged ≥65 years account for the fastest-growing population in industrialized countries, the number of patients with EORA will definitely increase over the next decade.

Various investigators have reported the clinical features of EORA. Both large and small joints are affected more frequently initially at onset, and serological tests show equal or slightly lower percentage of positivity of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody in individuals with early EORA than in those with early younger-onset RA [10, 18‐20]. Individuals with early EORA have higher disease activity scores, erythrocyte sedimentation rates, and C-reactive protein levels than early younger-onset RA [10, 18]. An explosive onset of shoulder arthritis, resembling polymyalgia rheumatica (PMR) is observed in 13–23 % of patients with early EORA [10, 18, 19]. Differentiation between anti-CCP antibody-negative EORA with PMR-like onset and PMR can be difficult and requires careful follow-up [21].

Clinical trials and biologic registries identified the characteristics of adverse drug reactions (ADRs) of bDMARDs. The main ADRs common to all bDMARDs in patients with RA in general are systemic disorders and administration-site conditions, infection and infestations, nervous system disorders, respiratory, thoracic, and mediastinal disorders, and skin and subcutaneous tissue disorders [34‐38]. Among these, infection and infestation and thoracic and mediastinal disorders are usually at the top of the list of serious ADRs with high incidence rates in patients receiving bDMARDs. In addition, malignancy, blood and lymphatic system disorders, immune system disorders, and gastrointestinal perforation, although less common, are considerable ADRs during treatment with bDMARDs.

Several studies have reported the overall safety of bDMARDs in elderly patients compared with younger patients. Sub-analyses of RCTs showed comparable incidence rates of adverse events between patients aged <65 and ≥65 years [28, 39, 40]. Some observational studies indicated an increased risk for adverse events or infections in elderly patients treated with TNF inhibitors compared with younger patients [26, 41], while other studies reported a similar safety profile between the two groups of patients [22, 42]. Such discrepancies could arise from differences in study design, study population, types of events analyzed, length of observation period, and statistical methods.

Population-based studies showed that patients with RA are more susceptible to infection compared with non-RA individuals [43‐45]. Hazard ratios (HRs) of infection in patients with RA were between 1.45 and 1.83, depending on the definition of infections [44], and the risk ratio of hospitalized infection in patients with RA or psoriatic arthritis was 2.7 compared with non-RA population [45]. Older age was a significant risk factor of infection or serious infection in patients with RA [43, 46]. A study using health administrative data of people aged ≥66 years in Canada showed that the most frequently occurring events included respiratory infections, herpes zoster, and skin/soft-tissue infections. Higher comorbidity, rural residence, markers of disease severity, history of previous infection, and use of glucocorticoids, TNF inhibitors, and some DMARDs or immunosuppressants were significant risk factors of serious infection [47]. In regard to the risk of serious infection associated with the use of oral glucocorticoids in older patients (≥65 years of age) with RA, the current and recent doses have the highest impact on current risk, but doses taken up to 2.5 years ago are also associated with increased current risk [48]. Use of glucocorticoids doubled the incidence rates of serious bacterial infections in Medicare beneficiaries aged ≥65 years with RA, with clear dose-response relationships and more impact during 1–90 days after treatment initiation compared with >90 days [49]. These data indicate that infection is the primary concern in elderly patients with RA, who are initiating treatment with bDMARDs.

Observational studies comparing RA patients who used TNF inhibitors and conventional DMARDs showed increasing age as an independent risk factor for serious infections [50‐52]. This was also the case with pneumonia in patients who were given infliximab [34] as well as serious infection in patients given etanercept [38], adalimumab [53], or tocilizumab [54] in the all-cases postmarketing surveillance programs implemented in Japan. Although the crude rate of infection increased markedly with increasing age in the group starting TNF inhibitors and that starting conventional DMARDs, the adjusted HR of the TNF inhibitor group vs the conventional DMARDs group was similar across the age groups [52]. Similarly, no increase in the risk of serious bacterial infections was observed among the initiators of TNF inhibitors in elderly patients with RA compared with initiators of MTX after adjusting for covariates [49]. There is not enough evidence for the safety of non-TNF bDMARDs in elderly patients with RA including EORA. An analysis of the Medicare claims database of patients with RA revealed the comparative risk of hospitalized infection during treatment with various bDMARDs. Patients aged ≥65 years accounted for ~30 to 50 % of the patient population in this study. The overall incidence rate of hospitalized infection was 15.3/100 patient-years. After adjusting for infection risk score and other potential confounders, infliximab (HR 1.39, 95 % CI 1.21–1.53), rituximab (HR 1.36, 95 % CI 1.21–1.53), and etanercept (HR 1.24, 95 % CI 1.07–1.45) users had a significantly higher hazard of hospitalized infection compared with abatacept users [55].

Atherosclerosis is a common age-related comorbidity and an important RA-related comorbidity among patients with RA. Various studies have demonstrated the risk of cardiovascular disease in RA populations [57‐60]. An observational study of the registry of North America found that coronary artery disease, myocardial infarction, stroke, and hypertension were more common among individuals with EORA (mean disease duration; 5.3 years) compared with disease duration-matched individuals with younger-onset non-elderly RA [16]. Interestingly, a Swedish cohort of early RA showed differential risks for cardiovascular events and mortality through 10 years between patients with RA with disease onset before 65 years and after 65 years of age. In the elderly-onset population (>65 years of age), good disease control in terms of disease activity and physical function reduced cardiovascular event risk, and the use of glucocorticoids resulted in more cardiovascular events and poorer survival [61]. In the non-elderly-onset population (≤65 years of age), inadequate control of inflammation and presence of RF or the anti-CCP antibody were associated with cardiovascular events. These findings are in line with the report that the risk for myocardial infarction was reduced in middle-aged patients with RA who responded well to TNF inhibitors [62]. According to the EULAR Task Force, patients with RA-related comorbidities such as cardiovascular disease may undergo intensive treatment [3]. This may be the case with EORA, but further investigation is required to establish an appropriate management strategy.

ILD is an extra-articular manifestation of RA, and is associated with mortality [63, 64]. Existence of ILD should be examined before treating patients with EORA, as the age at the time of diagnosis of RA was a risk factor for the development of ILD in a Mayo Clinic cohort (HR: 1.41 per 10-year increment in age, 95 % CI 1.11–1.79) [64]. This study showed that the risk for death in RA patients with ILD was three times higher than in RA patients without ILD. The median survival after the ILD diagnosis was only 2.6 years. The British Society for Rheumatology Biologics Register also showed that patients with RA-associated ILD were older than those without ILD [65]. A prospective monocentric Japanese registry of EORA (Choju registry of rheumatoid arthritis treated with non-biologic disease-modifying antirheumatic drugs and biologics in elderly patients in Japan [CRANE]; “Choju” is a Japanese word meaning longevity) found that pre-existing ILD was observed in 25 (16.6 %) of 151 patients with EORA; RA-associated ILD deteriorated over a relatively short period in 4 of the 25 patients and one patient without pre-existing ILD developed organizing pneumonia and pleuritis. All five patients were receiving csDMARDs and had high disease activity when ILD worsened; 0.5–1 mg/kg/day of prednisolone (PSL) was administered, and four patients recovered, but one died of exacerbation of ILD at week 28 of the observation period [66]. The presence of ILD has significant impact on mortality of patients with RA. Respiratory diseases and malignancy were two major causes of death followed by cardiovascular diseases in a large Japanese cohort. Pneumonia and ILD accounted for 50 and 46 % of the respiratory diseases, respectively [67].

Treatment with bDMARDs in RA patients with ILD is challenging. In patients with RA-associated ILD, mortality following treatment with anti-TNF therapy is not higher than that with traditional DMARDs [65]. However, chronic lung diseases including ILD is a well-established risk factor of infection in patients with RA [46, 51]. Rheumatologists sometimes hesitate to use MTX in patients with RA with ILD, and treatment with glucocorticoids is commenced. Coexistence of chronic lung diseases, older age, and concomitant use of glucocorticoids can further increase risk for infection or serious infection. Hence, the benefit-risk balance of bDMARDs in patients with ILD should be evaluated carefully before starting treatment [50, 68].

Frailty is a key concept in geriatric medicine and commonly occurs in older adults [69]. The common definition of frailty uses five criteria, which include weight loss (or loss of muscle), slow walking speed, exhaustion (or fatigue), muscle weakness, and low levels of physical activity. Patients are considered frail if three or more of the five criteria are met. Patients with a score of 1 or 2 are considered to be pre-frail, and a score of 0 indicates that the person is robust or not frail [70]. There are differences in the social, psychological, and physical functioning levels of elderly patients among the three stages of frailty [71]. Various chronic diseases including osteoarthritis, pulmonary disease, cardiovascular disease, stroke, chronic kidney disease, sarcopenia (the age-related loss of skeletal muscle mass), depression, and cognitive impairment are major risk factors of frailty [72‐74]. Frail individuals are at an increased risk for negative health outcomes such as functional decline, falls, institutionalization, pressure ulcers, delirium, incontinence, malnutrition, and mortality (Fig. 1). Although the impact of frailty on mortality of elderly patients with RA is unclear, a recent observational study for patients with osteoarthritis showed that frailty and related geriatric syndromes (i.e., disability of daily living, poor morbidity, visual impairment, cognitive impairment, hearing impairment, urinary incontinence, and low social support) enhanced the risk for long-term mortality of elderly patients [75].

Patients with advanced elderly RA are at a higher risk for progression to frailty because they are more likely to have functional decline, depression, cognitive impairment, falls, malnutrition, and polypharmacy [76‐81]. To prevent progression to irreversible geriatric syndromes, non-frail patients with EORA, who are aging successfully, should undergo intensive treatment using the treat-to-target strategy, and pre-frail and frail patients with EORA should be treated with the aim of returning to a non-frail or pre-frail stage, respectively (Fig. 1). Physical exercise may be also an important aspect of treatment strategy of EORA to facilitate maintaining functional capacity in daily life because it provided various beneficial effects including increase of muscle strength, maintenance of normal bone mineral density, and reduced risk of cardiovascular disease in patients with non-elderly RA [82‐85]. However, treating frail patients is usually difficult and complicated because they commonly have a variety of age-, RA-, and treatment-related comorbidities and are prone to progress to an irreversible stage of disability. In addition, physicians should avoid polypharmacy in this clinical setting because a number of potentially inappropriate medications may induce ADR, drug–drug interactions, and nonadherence in older adults and are associated with serious problems such as delirium, gastrointestinal bleeding, falls, and fracture [86‐89].