Autoimmunity Reviews 19 (2020) 102528

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Autoimmunity Reviews
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Rheumatoid arthritis in the elderly: Characteristics and treatment T

considerations
⁎
Lina Serhala, , May N. Lwina, Christopher Holroydb, Christopher J. Edwardsa
a
Department of Rheumatology and NIHR Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, UK
b
Department of Rheumatology, University Hospital Southampton NHS Foundation Trust, Southampton, UK

A R T I C LE I N FO A B S T R A C T

Keywords: The elderly rheumatoid arthritis (RA) population consists of both elderly-onset RA that manifests after the age of
Rheumatoid arthritis 60 and individuals diagnosed with RA early in life who age naturally to become members of this group. The
Elderly onset elderly RA population is expanding due to both increased life expectancy and an increased incidence of elderly
Elderly onset RA. Elderly onset RA seems to have a characteristic clinical pattern and perhaps biological profile different
Biological age
to that of early onset RA. The management of RA in elderly patients can be challenging, as robust treat-to-target
Comorbidities
Treatment
approaches must be balanced against the adverse events due to increased comorbidities in old age. This produces
a tendency to prefer less aggressive treatment in elderly RA patients in clinical practice. Despite the concerns
about adverse events, there is limited evidence on the best way to approach RA in this population, as elderly
patients are often not well presented in the clinical trials. Herein, we review the literature to assess the efficacy
and safety of RA therapies in this age group. We then suggest a tailored approach that can be adopted in clinical
practice, based on the disease severity and risk profiles of elderly RA patients.

1. Introduction comorbidities than patients with young-onset RA, perhaps due to the
effect of both RA and older age on the immune aging process [8].
Rheumatoid arthritis (RA) is a systemic autoimmune disease pri- Elderly onset RA seems to have a characteristic pattern with more
marily affecting synovial tissue and leading to joint destruction and acute onset, systemic involvement and worse functional outcomes than
disability [1]. The population of elderly patients with RA consists of young onset RA [9]. Therefore, weighing the benefits of a robust treat-
patients with elderly onset RA that manifests after age 60 and elderly to-target RA approach against the risks of adverse events due to in-
patients who presented with young onset RA earlier in life [2]. The creased comorbidities is challenging in this age group (Fig. 1). Concerns
elderly RA population is expanding, mainly due to population aging about adverse events may influence therapeutic decisions with clin-
with increased life expectancy and to an increasing incidence of elderly icians often preferring a less aggressive approach in elderly patients
onset RA [3,4]. [10]. Despite these concerns there is limited evidence on the best way
The immune system changes with age through a process known as to approach treatment as elderly patients are often not well represented
immunosenescence. There is growing evidence that the immune system in clinical trials due to age restrictions or to the presence of co-
in RA patients undergoes accelerated and premature aging [5]. The morbidities, such as infections, cancers and renal, liver and lung dis-
aging process affects both the innate and the adaptive immune systems. eases [11].
The innate immune system becomes non-specifically active with age, We have reviewed the literature to determine whether elderly onset
thus contributing to increased chronic inflammation and comorbidities RA patients have a unique biological profile that might suggest specific
[6]. The adaptive immune system becomes functionally defective and therapeutic strategies and whether RA therapies in this age group dis-
undergoes phenotypical changes with age, contributing to the break- play a particular benefit-risk profile when assessed in real-world cohort
down of immunological tolerance which contributes to an increased studies. Although additional clinical studies in elderly RA patients are
prevalence of autoimmune diseases [6]. Both healthy elderly in- needed, this review attempts to suggest a tailored approach that we
dividuals and RA patients of all ages share features of im- could adopt in our real-life daily clinical practice.
munosenescence that contribute to increased comorbidities [5] [7].
Patients with elderly onset RA have a higher prevalence of associated

⁎
Corresponding author.
E-mail address: lina_serhal@[Link] (L. Serhal).

[Link]
Received 9 January 2020; Accepted 13 January 2020
Available online 29 March 2020
1568-9972/ © 2020 Elsevier B.V. All rights reserved.
L. Serhal, et al. Autoimmunity Reviews 19 (2020) 102528

chronic tissue inflammation or ‘inflammaging’ and increased suscept-

ibility to infections, cancers and autoimmunity [7,12]. This is important
to consider when treating elderly RA patients, who are likely to have an
increased infectious risk.
The immune response to injury is defective in the elderly population
Fig. 1. Clinical approach in elderly RA patients. by favouring proinflammatory CD4+ T cells and M1 macrophages,
Tension often occurs when balancing the likely benefit of treating elderly RA which contributes to defective tissue repair, bone loss and increased
patients with active disease and increased risk of deterioration against the risk
arthritis susceptibility [14,15]. Moreover, increased levels of proin-
of adverse events due to comorbidities.
flammatory cytokines such as IL-6 and TNFα is predictive of mortality
in healthy elderly individuals and contributes to some diseases in aged
2. Is the immune system different as we age? individuals [14,16]. For instance, TNFα plays a direct role in the pa-
thogenesis of atherosclerosis, type 2 diabetes mellitus and Alzheimer's
The immune system is highly susceptible to the aging process, also disease, whereas high levels of IL-6 may be a risk factor for throm-
known as immunosenescence [7]. This immune aging is associated with boembolic events in aged individuals [14].
increased susceptibility to infections, cancer and autoimmune diseases
such as rheumatoid arthritis (RA) [7,12]. 3. RA and immunosenescence

2.1. Immunosenescence RA is characterised by inappropriately accelerated im-

munosenescence, which is present early in the RA disease course, and is
Aging affects all cells of the immune system but T cells appear to be independent of the disease duration [6,13]. The decline of thymic
the most prominently affected [6]. The emergence of senescent T cells output, loss of T cell diversity and T cell aging are premature by 20 to
in the periphery is a physiological aging process demonstrated in 30 years in RA compared to age matched healthy individuals (Fig. 2)
healthy individuals. In fact, the generation of new T cells declines with [7,5,13].
age. To compensate for this decline, the T cells in the periphery con- At a cellular level, the hallmark features of immune aging in RA
tinuously proliferate and subsequently become exhausted and senescent include: i) premature shortening of chromosomal telomeres with each
[5]. Senescent T cells are characterised by a contracted T cell receptor cell division of all T cells including naïve cells, eventually leading to cell
(TCR) repertoire and loss of CD28 expression (Fig. 2) [5]. In fact, the cycle arrest with impaired clonal expansion, cellular senescence with
presence of CD28 on T cells plays a pivotal role in self-tolerance when it impaired regeneration and altered cellular function [13,17], ii) decline
binds to the B7 molecule on dendritic cell surface [5]. Hence, the in the quality and efficiency of DNA repair, enhancing progressive ac-
presence of CD28 negative T cells (CD28- T cells) contibutes to the cumulation of DNA damage and ultimately premature senescence or
reduced immune tolerance with age and subsequenlty increased in- apoptosis that possibly leads to lymphopenia [17], iii) increase of
cidence of autoimmune diseases, such as RA where a similar T cell CD28- T cells promoting more severe and systemic disease where CD28-
phenotype is described [5,13]. This could be an interesting field of T cells are markedly increased with extra-articular complications and
future studies to assess whether we could stratify elderly RA patients to found to be associated with atherosclerotic disease in RA [5], iv) dis-
specific therapies, for instance T cell targeted RA therapies. turbed induction of regulatory CD4+ T cells [15] and v) metabolic
reprogramming of the dysfunctional senescent T cells contributing to a
2.2. Reduced adaptive but increased tissue-damaging innate immunity proliferation bias towards effector T cells with proinflammatory func-
tions [7]. This could represent an important area to direct future studies
Immunosenescence is associated with reduced adaptive immunity to assess the possibility of resetting the immune system, perhaps by
but increased tissue-damaging nonspecific innate immunity leading to repopulating it with young and adaptable lymphocytes [13].
Whether immunosenescence in RA is primary or secondary to
chronic inflammation is not clear. However, premature aging of naïve
as well as memory T cells and the faster telomere erosion of healthy
individuals who share HLA-DR4 with RA patients raise the hypothesis
of probable primary immune aging in RA [18].

4. Is RA different in old age?

Both elderly individuals in the general population and RA patients

of all ages show senescence-associated features of the immune system
(Fig. 2). It is well known that molecular changes in RA exist years be-
fore RA onset and although the disease aetiology is not yet fully un-
derstood, it results from exposure to a combination of environmental
factors in genetically susceptible individuals [19]. However, the reason
why RA starts at different ages is not clear. The population of elderly
onset RA is expanding and represents one third of the total RA popu-
lation [2]. In fact, a study from the US showed that over one decade, the
Fig. 2. Immunosenescence changes with age and RA.
The emergence of senescent T cells in the periphery is a physiological aging
incidence of elderly onset RA has increased and the average age of RA
process demonstrated in healthy individuals. In fact, the generation of new T onset increased from 50 to 60 years [2].
cells declines with age. To compensate this decline, the mature T cells in the
periphery continuously proliferate and subsequently become exhausted and 4.1. Elderly onset versus young onset RA (Fig. 3)
senescent. This process, known as immunosenescence, is accelerated in RA
patients. Patients with RA show features of premature immunosenescence by 20 Elderly onset RA appears to have a characteristic presentation with
to 30 years. more male prevalence, acute onset, systemic features, large and prox-
Adapted from Lindstrom et al. [5]. imal joint involvement with polymyalgia rheumatica-like symptoms,
CD28- CD28 negative; T reg Regulatory T cells; RA Rheumatoid arthritis. less rheumatoid factor positivity and worse functional outcomes than

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L. Serhal, et al. Autoimmunity Reviews 19 (2020) 102528

Fig. 3. Characteristics of elderly RA population. * Elderly RA population includes patients with elderly onset RA and young onset RA diagnosed earlier in life. RF
Rheumatoid factor; ESR Erythrocyte Sedimentation Rate; RA Rheumatoid arthritis; PMR Polymyalgia rheumatica; IL-6 Interleukin 6; CRP C-Reactive protein; TNFα
Tumour necrosis factor α; ACPA Anti-citrullinated Protein Antibodies.

young onset RA [9]. Elderly onset RA may also have a different makes it complicated, but crucial to look at, when often complex
proinflammatory cytokine profile compared to young onset RA; in a treatment is considered in elderly RA patients.
Taiwanese cohort, elderly onset RA patients showed significantly
higher IL-6 and lower TNFα levels in peripheral blood. High IL-6 levels 5.1. Geriatric Syndromes (GS)
were associated with male preponderance, high CRP and PMR-like
symptoms, whilst high TNFα levels were associated with constitutional The term GS is a well-known geriatric term and is defined as mul-
symptoms and anti-citrullinated protein antibody (ACPA) positivity tifactorial health conditions that make an elderly individual vulnerable
[20]. Although it is difficult to draw conclusions from one study, this to health or social challenges, and thus GS accounts for unsuccessful
constitutes an important field for future studies to assess the efficacy of aging and frailty of elderly people [28]. It consists of multiple and in-
a stratified approach to selection of biological therapies in this age terrelated factors such as cognitive impairment, depression, fall, in-
group. continence, sensory limitations and malnutrition [29].
In addition, ESR increases with age and this could interfere with the
interpretation of the RA disease activity score DAS28 (ESR). Although 5.1.1. Geriatric syndrome and RA
DAS28 (ESR) has been found to be reliable to assess disease activity in A strong interrelation between GS and RA exists. RA is frequently
moderate to severe RA regardless of age and sex, remission rates could associated with depression, cognitive impairment and falls, and RA
be underestimated in elderly men with DAS28 (ESR) less than 3.1 [21]. patients have higher disability than age matched populations [30–32].
Higher disease activity and longer-term RA are found to be risk factors
4.2. Elderly onset RA: Different environmental exposure/genetic for developing GS in elderly patients [29]. In addition, anaemia of
associations? chronic disease is more frequently encountered in elderly RA patients
with GS, which further enhances functional impairment and cognitive
It seems likely that the current older population have been exposed dysfunction, leading to further disability and a trend towards increased
to different environmental factors than the young population. Smoking depression in elderly RA patients [29,33]. Thus, GS in elderly RA
and delayed menarche are known risk factors for the development of contributes to malnutrition, which in turn worsens RA activity and
RA [22,23]. Smoking consumption in Britain increased markedly until functional outcomes [34]. One could therefore suggest that efficient RA
it reached a peak of 50% in 1970; afterwards, it began to fall drama- treatment would help to improve physical and mental outcomes in el-
tically to 25% in 1998 and then steadily down to 14.4% in 2018 derly RA patients.
[24,25]. Likewise, menarche onset showed a downward trend over
decades, around 3 to 4 months per decade [26]. The genetic associa- 5.1.2. Cognitive dysfunction in RA
tions with RA were analysed after stratification of patients by age [27]. Chronic systemic inflammation such as that seen in RA is an im-
This showed that HLA-DRB1 phenotype frequencies differ between portant risk for developing cognitive dysfunction, which is found to be
early onset and elderly onset RA [27]. This could reflect the fact that associated with more functional limitations, depression and pain
different combinations of environmental and genetic factors may have [35,36]. In fact, RA is associated with an increased risk of Alzheimer's
contributed to the development of, and increased incidence of elderly disease and vascular dementia, particularly in elderly patients who
onset RA. themselves have more cardiovascular risk factors, hence this can further
increase the risk [37,38]. Moreover, it is suggested that RA treatment
5. Biological age and RA has a protective effect on cognitive function [37]. This is supported by
real-world data from Germany where the mental health of RA patients
Biological age reflects the degree of physical and mental function- significantly improved with effective treatment (assessed with Short
ality of the elderly when compared with chronologically aged in- Form-36 Mental Component score that includes vitality, social func-
dividuals, and it differs widely among the elderly population. tioning, role-emotional and emotional well-being) [39]. Nevertheless,
Unsuccessful aging occurs when biological age exceeds chronological cognitive dysfunction could be underestimated in RA, which might
age [17]. Multiple factors count for this discrepancy, including geriatric affect the compliance and subsequently the response of elderly patients
syndromes, comorbidities, polypharmacy and frailty (Fig. 3). This to treatment [29].

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L. Serhal, et al. Autoimmunity Reviews 19 (2020) 102528

5.2. Comorbidities the general population with a HR of 9.0 (CI 95% 4.0–19.9) [59]. RA-
related ILD is associated with a significantly increased mortality when
The prevalence of comorbidities is higher in the general elderly compared to RA patients without ILD [60]. The risk of developing
population but is even higher in those with elderly onset RA [17,40,8]. chronic obstructive pulmonary disease (COPD) in RA is not well es-
Higher numbers of comorbid conditions in RA patients is associated tablished; a meta-analysis demonstrated a statistically significant in-
with lower response to RA treatment and greater mortality risk, perhaps creased risk of subsequent development of COPD in RA patients, where
indicating that comorbidities in RA might be linked to autoimmune the HR in RA patients versus control group was 2.0 (CI 95% 1.6–2.5)
mechanisms [39,41,42]. [61]. Smoking, which is an established risk factor for RA, might
strongly contribute to this association. This further affects the disease
5.2.1. Cardiovascular disease management in elderly patients, where risks and benefits of RA thera-
It is well established that atherosclerosis and eventually cardiovas- pies must be carefully weighted.
cular disease are accelerated in RA [43]. Cardiovascular diseases lar-
gely contribute to the increased mortality in RA [44]. In fact, cardio- 5.3. Polypharmacy
vascular morbidity is doubled and cardiovascular mortality is increased
by 60% in RA patients, with congestive heart failure and ischemic heart Polypharmacy is frequently encountered in elderly patients with RA
disease constituting the main contributors to overall increased mor- as a result of increased comorbidities. This makes it difficult to optimise
tality in RA [45–47]. Inflammatory arthritis and atherosclerosis are the often-complicated RA treatment protocols in this age group, with an
thought to have the same inflammatory pathogenesis, further supported increased likelihood of drug interactions, adverse events and contra-
by the observed reduction in cardiovascular morbidity with effective indications due to hepatic and renal dysfunction. Nevertheless, it is
treatment of RA patients in population-based studies [48,49]. Thus, crucial to weigh risks and benefits before initiating treatment in elderly
inflammation is a well-known cardiovascular risk, particularly with RA patients, where effective treatment has been proven to reduce
increased age where age-related elevated levels of proinflammatory mortality, not least by reducing the need for steroids [41].
cytokines and CRP might be partly responsible for the increased car-
diovascular risk [17]. Moreover, traditional cardiovascular risk factors 6. Do we treat elderly patients in the same way as young patients
and the use of steroids and non-steroidal anti-inflammatory drugs with RA?
(NSAIDs) contribute to the increased cardiovascular risk in RA patients.
Despite this cardiovascular risk management of RA patients remains Increased age remains a significant barrier to a successful treat-to-
unsatisfactory [43,50]. target approach in elderly patients with RA. A survey conducted in the
US concluded that the treatment recommendations of rheumatologists
5.2.2. Infections are affected by age, preferring less aggressive treatment for elderly RA
Infection is a major concern in RA and is one of the leading causes of patients [10]. Likewise, data from the British Society for Rheumatology
premature death in RA patients, especially with increased age [51,52]. Biologics Register for Rheumatoid Arthritis (BSRBR-RA) showed that
Age has been demonstrated to be an independent risk factor for serious young patients with RA have higher rates of switching between
infections in patients with RA [52]. In fact, the features of im- bDMARDs than elderly patients, regardless of the biologic class [62].
munosenescence leading to defective protection against infections and Although data from a large Early RA Network (ERAN) cohort of patients
associated immune compromising comorbidities in RA are further ac- found that the time for first outpatient visit and the initiation of
celerated in elderly patients [6,40]. Elderly onset RA patients often treatment within 3 months was not biased by age, elderly patients were
have greater disease activity leading to early disability and eventually exposed to more steroid use and monotherapy with csDMARDs rather
increased immobility, which is a strong risk for infections such as re- than combinations of csDMARDs or bDMARDs over 2 years than their
spiratory and urogenital infections [8,53]. In addition, the use of im- younger counterparts [63].
munomodulatory treatment further increases the risk of infection in RA A population-based study demonstrated that age is a significant
patients [54]. predictor of failure to use any DMARDS (synthetic or biologic) in the
first 12 months, where half of the RA patients aged between 65 and 75
5.2.3. Malignancies and less than third of RA patients aged more than 75 years received
Cancer contributes to the increased mortality in RA patients [44]. DMARDs [64]. Although the use of methotrexate was found more
RA is an independent risk factor for developing malignancies where commonly in elderly onset compared to young onset RA in another
overall malignancy risk is increased compared to the general popula- cohort study, the weekly dose was considerably lower [40]. Similarly,
tion, particularly lymphoma and lung cancer [55,56]. The immune the use of multiple csDMARDs or bDMARDs in elderly RA patients was
aging process in RA might contribute to this risk, notably due to the markedly lower compared to young patients, where the decision was
presence of chronic inflammation and defective DNA repair [17]. The not related to the disease activity, the disease duration or the presence
malignancy risk attributable to the use of immunosuppressant therapy of comorbidities [40,42,65]. However, the use of prednisolone is
in RA is debatable. While the use of conventional synthetic disease- slightly more frequent in elderly onset RA when compared to young
modifying anti-rheumatic drugs (csDMARDs) and biological DMARDs onset RA, even though its use has been shown to increase cardiovas-
(bDMARDs) in RA seems to be safe overall with regards to malignancy, cular risk in elderly patients [41,42].
the risk of melanoma may be slightly increased [54]. Accordingly, it is
important to consider this when treating rheumatic diseases, particu- 7. Do RA therapies work in elderly patients?
larly in elderly patients since the incidence of many cancer types
characteristically increases with age [57]. There is a growing evidence that the majority of RA therapies are
similarly effective in elderly when compared to young patients.
5.2.4. Lung disease Conventional synthetic DMARDs display a similar efficacy profile
Lung disease is prevalent in RA patients and may be related to the among all age groups [66]. However, a lower maintenance dose of
disease itself, comorbidities, drug therapy or a combination of these methotrexate might be effective in elderly patients and thus dose ad-
factors. It is suggested that chronic lung injury in genetically predis- justment might be sometimes required [67]. This is mainly owing to
posed individuals leads to RA-related lung changes, where chronic in- age-related changes in pharmacokinetics with subsequent reduced renal
fections and smoking are important contributing factors [58]. Inter- clearance [66,67]. With regards to bDMARDs, it seems that the efficacy
stitial lung disease (ILD) is increased in RA patients when compared to is likely to be comparable among all age groups. In fact, a large

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L. Serhal, et al. Autoimmunity Reviews 19 (2020) 102528

Japanese cohort of RA patients showed similar clinical improvement at important to mention that steroid use of more than 5 mg/day is asso-
48 weeks and drug maintenance rates between patients with young ciated with increased cardiovascular disease risks and eventually mor-
onset and elderly onset RA after initiation of bDMARDs [68]. tality in a dose-dependent manner, and is a potential risk for cognitive
Tumour Necrosis Factor inhibitors (TNFi) appear to be effective in dysfunction in the elderly [38,41,42]. Therefore, increased age should
elderly patients with RA, although a large cohort of RA patients from not deprive elderly RA patients of effective treatments if there are no
the BSRBR showed that elderly patients of 75 years or more were less contraindications, to help reduce the need for steroids and improve
likely to discontinue TNFi monotherapy due to inefficacy and more functional outcomes, thus reducing cardiovascular risk and overall
likely to discontinue therapy due to adverse events, when compared to mortality.
younger population [69]. This may reflect a decline in immunogenicity
associated with immune aging changes. In addition, post-hoc analysis of 9. Are adverse events associated with treatment the same for
four controlled studies and two long extension studies of etanercept in elderly patients with RA?
early and late stage RA showed that, although elderly patients tended to
have a less robust response than young patients, the pattern of clinical There is increasing evidence that RA therapies are similarly toler-
and radiological response was comparable and sustained in both age able and safe in elderly compared to young RA patients.
groups [70–73]. Etanercept combined with methotrexate resulted in a Hydroxychloroquine appears to be the least toxic csDMARD in elderly
greater efficacy than either therapy alone in elderly patients with late RA patients [93]. Unlike the length of use and the cumulative dose,
stage RA but they were equally effective in elderly patients with early increased age was not found to be an independent risk for development
RA [73–75]. Notably, elderly RA patients tended to have higher dis- of hydroxychloroquine retinopathy [94]. Methotrexate seems to be
ability at baseline than young patients but showed greater functional better tolerated than sulfasalazine in elderly RA patients, where after
improvement with etanercept [73]. Nontheless, etanercept displayed a 5 years, almost three quarters of patients continued methotrexate and
similar efficacy profile among all age groups when results of a larger half continued sulfasalazine [93]. The drug discontinuation was mainly
cohort of patients from five open-label and four double-blind rando- due to gastrointestinal, hepatic, cutaneous and possibly lung side effects
mized controlled trials were analysed [76]. Likewise, real-world data with methotrexate and gastrointestinal side effects with sulfasalazine
analysis from different countries including British, Swiss and US re- [93].
gistries proved that the efficacy of TNFi's was similar in young and The safety of biological DMARDs appears similar for elderly and
elderly RA patients, though slightly less significant in elderly patients young RA patients, where most evidence exists for TNFi and abatacept.
from the Dutch RA monitoring registry [77–80]. Nevertheless, elderly In fact, Swiss and Dutch biologic registries have provided a reassuring
RA patients of more than 70 years from the Swiss cohort showed clin- safety profile of TNFi in elderly RA patients that is comparable to
ical but not functional improvement with TNFi, perhaps due to asso- younger patients [78,80]. Although data from controlled clinical trials
ciated comorbidities and osteoarthritis [78]. of etanercept showed that the rates of serious adverse events, serious
Abatacept displayed a favourable benefit profile in elderly RA pa- infection episodes and cancer were slightly higher in the elderly group,
tients with the highest retention rate among seven other bDMARDs for the risk did not increase beyond that imposed by increased age and
clinical response and tolerability in a Japanese multi-centre cohort comorbidities [73,76]. Abatacept showed the lowest discontinuation
[81]. Furthermore, a French population-based study demonstrated that rate after adverse events in elderly patients enrolled in a Japanese
elderly RA patients of more than 75 years who had higher disease ac- registry, perhaps due to a steroid sparing effect, with a one third re-
tivity at baseline than young patients benefit as much, if not more from duction of steroid users receiving abatacept demonstrated in a French
abatacept over a 2-year follow-up period [82]. Likewise, oral Janus cohort study [81,82].
Kinase inhibitors (JAKi) namely tofacitinib and baricitinib displayed Nevertheless, the risk of infection with bDMARDs might increase in
similar efficacy in young and elderly RA patients in recent clinical trials elderly RA due to the decline of the immune system over the years. In
[83,84]. fact, the increased risk of serious infection with TNFi in RA patients
The efficacy of tocilizumab and rituximab may be less in elderly RA enrolled in the German biologic register was associated with increased
patients. A French study showed that among 222 RA patients treated age of more than 60 years, active disease, high steroid use and co-
with tocilizumab, 61 patients were more than 65 years and had sig- morbidities such as chronic renal and lung disease [53]. Furthermore,
nificantly lower clinical response and remission rate when compared to the presence of comorbidities was a predictor of adverse events at the
young patients (40% vs. 61% and 28 vs 46%, respectively; p < .05) start of bDMARDs based on the findings of European biologic registries
[85]. Another French study analysed the efficacy of rituximab and [95]. The risk of subsequent infection with bDMARDs among RA pa-
showed that, although all age groups displayed similar clinical re- tients who had previous infection on TNFi was assessed in a large co-
sponses, patients between 65 and 75 years were more likely to respond hort study from the US (mean age across biologic exposure was 64 to
than patients of more than 75 years over a 1-year follow-up period (OR 69 years) [96]. This showed that the risk, when compared to that of
3.81, 95% CI 1.14–12.79) [86]. Nevertheless, larger studies are needed infliximab, was significantly lower with abatacept (HR 0.80, 95% CI
before drawing concrete conclusions in this regard. 0.64–0.99) and Etanercept (HR 0.83, 95% CI 0.72–0.97) [96]. It is
difficult to predict the infectious risk associated with TNFi in elderly RA
8. Do therapies for RA improve comorbidities? patients, but this must be balanced against the risks of high steroid use,
active disease, presence of comorbidities and previous infection history
Since RA and atherosclerosis share a similar inflammatory patho- that are more commonly encountered in elderly patients.
genesis, it is suggested that RA treatment might have an anti-athero- Data for other bDMARDs are limited. Rituximab was associated with
genic activity [87,88]. In fact, a beneficial effect of methotrexate and numerically higher infection rates in elderly RA patients in a French
adalimumab on lipoprotein functions and macrophage cholesterol me- cohort study [86]. Likewise, tofacitinib and baricitinib were associated
tabolism has been demonstrated in vitro [89]. Furthermore, the risk of with numerically higher rates of serious infections and herpes zoster
cardiovascular disease seems to be higher in rheumatoid factor positive infections in elderly versus younger RA patients in the clinical con-
RA and is not just related to traditional cardiovascular risk factors [90]. trolled trials [83] [84]. Based on the summary of product character-
This might explain the reduced cardiovascular risk and overall mor- istics (SmPC), patients aged over 75 years starting on baricitinib might
tality with effective RA treatment described with methotrexate, TNFi use the reduced dose of 2 mg instead of 4 mg daily. Dose adjustment
and rituximab [41,43,49,53,91]. Nevertheless, the protective effect of does not seem to be required for other bDMARDs, but caution when
bDMARDs against congestive heart failure via their anti-inflammatory treating elderly RA patients, particularly women of more than 60 years
effect is controversial and needs further understanding [92]. It is with infliximab has been suggested. This was based on a large Swedish

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Fig. 4. Suggested flow chart of considerations when treating elderly RA patients.

Table 1
Suggested clinical approach in elderly RA patients.
Considerations Suggestions Details

I. General 1. Care when using DAS28(ESR) ESR commonly increases with age
2. Balance risk of steroids against other therapies Steroid use in elderly associated with increased CV risk and mortality
3. Vaccination as per guidelines Infectious risk likely to be increased in elderly
II. Low risk profilea Treat-to-target approach No evidence supports avoiding effective RA therapies solely on the basis
of increased age
III. Comorbidities
i) General profile Weigh benefits and risks of bDMARDs vs comorbidities Number of comorbidities is one of the strongest predictors of AEs with
biologics
ii) Cardiovascular disease 1. Address traditional CV risk factors Encourage smoking cessation, healthy lifestyle and regular gentle exercise
2. Consider statins Statins likely have anti-inflammatory effects
3. Avoid high dose steroids CV risk increased with doses of > 5 mg/day in dose-dependent manner
4. RA therapies generally safe RA therapies have a protective effect on IHD but effect on cardiac
function controversial
iii) Renal, liver and/or lung disease 1. Start low dose MTX and increase slowly Lower maintenance doses commonly required in elderly
2. Consider dose adjustment ie Baricitinib, reduced dose of 2 mg daily is recommended for elderly RA
aged 75 or more
iv) History of infection with TNFi Consider bDMARDs with short half-life Etanercept and Abatacept displayed lower risk of subsequent infection
compared to Infliximab [96]
v) History of cancer Nil specific but cervical screening for female patients on TNFi Increased reported cervical cancer in patients on Infliximab compared to
may be advisable bDMARDs naïve [97]
IV. Cognitive dysfunction Support elderly patients to improve adherence Growing evidence for protective effect of RA therapies on cognitive
function
V. Polypharmacy Consider dose adjustment. Caution with drug interactions.

RA Rheumatoid arthritis; DAS(ESR) Disease Activity Score (Erythrocyte Sedimentation Rate); IHD Ischaemic heart disease; SmPC Summary of product character-
istics; CV cardiovascular; bDMARDs biologic disease-modifying anti-rheumatic drugs; TNFi Tumour Necrosis factor inhibitors; US United States. MTX Methotrexate.
a
Low risk profile reflects elderly patients with no cognitive dysfunction, presence of comorbidities with subsequent polypharmacy or frailty.

population-based cohort study that reported an increased incidence of 11. Conclusion

cervical cancer with infliximab compared to bDMARD-naïve patients
and the general population and hence, enhanced cervical screening is To conclude, RA therapy seems to be generally effective and safe in
advised [97]. However, further clarification around this issue is re- elderly patients. Real-world data have shown that treatment of elderly
quired from other registry studies. RA patients is crucial although it remains unsatisfactory in clinical
practice. This is likely due to lack of evidence and concerns about ad-
verse events with often associated comorbidities, polypharmacy and
10. What clinical approach should we adopt? cognitive dysfunction. Hence, the therapeutic approach must be ba-
lanced against the risk profile of the elderly patients and careful se-
There is no unique approach to adopt but treatment must be tailored lection of the drug, adjustment of the dose and monitoring of the dis-
to the profile of elderly RA patients (Fig. 4). We have attempted to ease are required.
suggest a tailored approach that can be adopted in daily clinical prac-
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