Management of Inflammatory Rheumatic Conditions in the Elderly

Clément Lahaye; Zuzana Tatar; Jean-Jacques Dubost; Anne Tournadre; Martin Soubrier


Rheumatology. 2019;58(5):748-764. 

In This Article


Specificities of Initial Presentation in the Elderly

Most studies refer to older subjects without specifying whether the disease appeared after 60 years of age (elderly-onset RA, EORA) or at a younger age (young-onset RA, YORA). For this overview, the term EORA will be reserved for studies specifying an old age of onset. EORA has specific clinical and biological characteristics. The female predominance is less marked, disease onset more abrupt, morning stiffness prolonged and constitutional symptoms more severe than in YORA.[6] The differential diagnosis with PMR or microcrystalline arthritis is more challenging due to common proximal joint involvement.[7] EORA is associated with increased MRI-detected inflammation, but this effect of age is similar in controls, supporting the hypothesis of a general and non-disease-specific effect of age on MRI inflammation, possibly related to immunosenescence.[8]

Higher IL-6 and lower TNFα levels have been observed in EORA compared with YORA.[9] In the elderly population, high levels of TNFα are associated with an increased risk of hospitalization and death at 1 year.[10] EORA patients often present with higher DAS 28 and Ratingen scores at diagnosis,[11] increased inflammation and disability[12–14] and a greater number of comorbidities,[12] but less RF and ACPA positivity.[15]

Age and Treatment Effectiveness

Due to the lack of specific studies in the elderly, conventional synthetic DMARDs (csDMARDs) in combination with glucocorticoids (GCs) constitute the initial treatment for RA, as in younger subjects.[16,17] As the reference csDMARD, MTX remains the gold standard in EORA management. The rare studies investigating its efficacy in the elderly have not revealed decreased effectiveness of csDMARDs compared with YORA. Pooled data from 11 MTX clinical trials involving 496 RA patients revealed no effect of age or renal impairment on MTX efficacy.[18] In the Swedish Farmacotherapy (SWEFOT) trial, higher age was associated with an increased likelihood of EULAR response to MTX in patients with new-onset RA.[19] A retrospective series of 90 RA patients showed no impact of age on the efficacy of LEF.[20] Despite widespread use of GCs, particularly in elderly RA patients,[21] initial dosage, optimal treatment duration, tapering strategies and the timing and frequency of administration remain largely empirical.[22] Expert reports advocate as low a dose and as short a duration as possible, a fortiori in elderly and fragile subjects.[17]

Numerous studies have documented the effectiveness of biotherapies (mainly TNFα inhibitors, TNFi) in EORA (Table 1). In several registries, TNFi were found to be slightly less effective in patients aged >65 years in terms of improvements in disease activity,[23–25] radiographic damage,[15] functional recovery[26] and HR-QoL.[27] However, some registries have shown no effect of age on the response to TNFi[28] or radiological progression after 5 years of treatment.[11] Moreover, randomized controlled trials have demonstrated that the benefits in terms of clinical response and radiographic progression when adding etanercept (ETA),[29,30] infliximab or adalimumab[31] to MTX for RA treatment are maintained in the elderly population compared with subjects aged <65 years. In a post hoc study of the open-label period of three studies concerning ETA in RA, there were no substantial differences in efficacy for ETN patients ≥65 vs <65 years.[32]

Data on other biologics are scarce and inconsistent. Regarding rituximab, a prospective study found no effect of age on changes in DAS 28 at 8 months,[33] whereas in the French registry, patients aged >75 years were less likely to be good responders at 1 year.[34] Sekiguchi et al.[14] revealed no difference between YORA and EORA in achieving remission with abatacept as the initial DMARD, yet the functional remission rate was lower in elderly patients. These data are consistent with the Japanese and French registries, in which there was no age-related difference in effectiveness, respectively, 1 and 2 years after introducing abatacept.[35,36] Matsuda et al. showed as much benefit of abatacept in the elderly as in the younger patients regarding HR-QoL, disease activity and reduction of GC dose.[37] A retrospective study assessing tocilizumab in RA patients found a significantly decreased number of elderly patients with good EULAR response and remission at 6 months.[38] Concerning oral Janus kinase inhibitors, patients aged >65 years had similar response rates to patients aged <65 years after 3 months of tofacitinib and baricitinib for moderate to severe RA in a pooled analysis of phase 3 trials.[39,40]

Age and Adverse Drug Reactions

As both RA and ageing are associated with cardiovascular disease, malignancies, osteoporosis and infection, it may be difficult to determine the extent to which treatment is responsible for the occurrence of complications.[41] Older subjects are more susceptible to infectious complications, with most studies reporting a 2- to 3-fold higher risk of serious infections for those aged >65 years.[42]

MTX has been associated with serious AEs, such as major infections, hepatic failure, bone marrow depression and inflammatory pneumonitis. In a Canadian population-based study, increasing age was associated with an increased tendency towards MTX discontinuation in newly diagnosed RA patients.[43] As kidney failure and hypoalbuminaemia both increase the risk of severe MTX toxicity, a dose adjustment is often necessary in the elderly.[18,44,45] In a retrospective series of 90 LEF-treated RA patients (monotherapy or combination therapy) with 2 years of follow-up, the AEs and survival rates of LEF were equivalent between patients aged ≤65 years and those aged >65 years.[20] However, hypertension and unintentional weight loss related to LEF are of particular concern in the elderly.[46]

Regarding TNFi, several studies have pointed out high infection risk in the elderly (Table 1) particularly in cases of high comorbidity, elevated disease severity markers and previous infection.[42] In retrospective cohorts of RA patients treated with biologic originator DMARDs (boDMARDs), though drug discontinuation appeared similar between age groups; discontinuation was related mainly to AEs (specifically infections) in the elderly, whereas drug ineffectiveness was the main reason for treatment discontinuation in younger patients.[47–50] In a registry of RA patients treated with conventional DMARDs or TNFi, multivariate analysis revealed that TNFi use (risk ratio (RR) = 2.37; 95% CI: 1.11, 5.05; P = 0.026) and age (by decade RR = 1.82; 95% CI: 1.32, 2.52; P = 0.00031) were significant independent risk factors for serious infections.[51] A moderately increased absolute risk of serious infection has been reported after the introduction of TNFi, with no difference between age categories.[23,52–54] However, after multivariate adjustment for age, sex and comorbidities, most of the studies did not find an increased risk of serious infection associated with the initiation of TNFi therapy compared with non-biologic comparators,[55] even upon long-term follow-up[29,30,56] and irrespective of the inhibitor.[57]

Compared with TNFi therapy-naïve subjects, patients on TNFi therapy are more susceptible to tuberculosis reactivation, usually affecting extrapulmonary sites (pericardium, gastrointestinal, bone or lymph nodes).[67] Age >60 years for RA, history of tuberculosis and daily GC use ≥5 mg were significant risk factors for this complication.[68,69]

In addition, ageing RA patients are at particular risk of herpes zoster (HZ) infection. The incidence of HZ infection appears to be similar after initiating csDMARD or TNFi therapy, regardless of the inhibitor that is used.[70] Age and GC use are additional risk factors.[56,57] As a representative of the emerging class of Janus kinase inhibitors, tofacitinib seems to increase the risk of opportunistic infections such as tuberculosis and HZ infection.[71] Thus, the ACR recommends the HZ vaccine for all RA patients aged ≥50 years, before the introduction of boDMARDs due to it being a live vaccine.[72]

Though data on other biologics are scarce, they suggest an increased risk of infection (Table 1). Concerning abatacept, two cohorts found no significant differences in treatment withdrawal rates due to AEs depending on age.[14,37] This outcome differed from the French registry, in which increasing age was associated with a higher AE-induced treatment discontinuation rate, especially in regards to severe infections.[35] In a Japanese registry, the elderly abatacept-treated group (>69.5 years) demonstrated higher incidence rate of discontinuation due to AEs in patients without concomitant use of MTX.[36] Concerning rituximab, even if one prospective study showed no effect of age on ADRs and serious ADRs,[33] other studies with long-term follow-up revealed that age >65 years is associated with a higher incidence of discontinuation rates due to serious ADR[73] or infections compared with age <65 years.[34] In a retrospective study pertaining to tocilizumab use in RA patients, drug maintenance was similar between elderly and younger RA patients. No differences were found according to age class.[38] In a pooled analysis pertaining to three randomized controlled trials and two open label extensions in tofacitinib-treated patients with moderate to severe RA, serious infections and AE-induced discontinuations are more common after 65 years of age.[39] Similar results were observed with baracitinib.[74] In addition to differences in the mode of action among DMARDs, the differing infectious risks may reflect an incomplete adjustment for infection risk factors in elderly RA patients (e.g. diabetes, malnutrition).

Among pharmacological risk factors for infection, the use of GCs plays a predominant role. Oral GC at doses ≥5 mg prednisone-equivalent are associated with a dose-dependent increase in serious infection risk, which is still present up to 2 years after discontinuing treatment.[55,56,67] Moreover, low GC doses (1–4 mg/day) have been shown to be associated with serious infections in biologics-treated patients, but not in non-biologic DMARD-treated patients.[56] Specific studies on the benefit/risk balance of GCs in the elderly will be particularly useful.

Elderly patients are at particular risk for cancer, and RA is associated with an overall increased incidence of cancer, especially Hodgkin's and non-Hodgkin's lymphoma,[75] and non-melanoma skin cancers.[76] Moreover, elderly RA patients who develop cancer have a higher mortality rate than subjects without RA after controlling for other comorbidities.[77] As biotherapies are suspected to play a role in carcinogenesis and tumour progression, cancer risk during boDMARDs treatment have been observed in numerous studies, with discordant results, particularly due to the disparate methodologies used (follow-up period, comparator, cancer type, etc.).[78,79] Notably, increased crude rates of cancer have been reported in EORA vsYORA patients undergoing TNFi treatment[23] or other biotherapies.[35] However, most of the studies did not reveal an increased overall cancer risk using TNFi[60,65,79,80] or other biologics[58,66] compared with csDMARDs in elderly patients. Although specific risks of haematological cancers[66] and non-melanoma skin cancer[63,81] have been reported in TNFi-treated patients compared with biologic-naïve patients, these studies were not specific to older subjects. Current knowledge advocates the monitoring of increased cancer risk in elderly patients, starting at diagnosis and continued a fortiori prior to and after biotherapy initiation.

RA is associated with an increased risk of early cardiovascular diseases.[82,83] Due to inflammatory mediators playing a role in the pathogenesis of cardiovascular diseases, TNFi were expected to exert a protective effect.[82] Though such a benefit was observed in a younger patient population,[84] elderly patients receiving TNFi exhibited a higher hospitalization rate for heart failure (HF) than patients on MTX,[85] but without increased mortality.[64] In a retrospective US cohort of RA patients, TNFi were associated with higher acute myocardial infarction risk compared with abatacept.[86] However, in another American database of RA patients starting TNFi or boDMARD treatment after MTX use, there was no elevation in HF risk among users of inhibitors, irrespective of prior HF. Oral GCs were associated with a dose-dependent increase in HF risk.[78]

Due to chronic inflammation, functional limitation and associated treatments, especially GCs, RA is associated with an increased risk of both fracture and sarcopenia. Besides traditional risk factors, such as low BMI or oral GC use, RA duration >10 years is associated with an elevated risk of hip fracture.[87] Due to the specific risk linked to prolonged GC use,[88] the ACR has established lifestyle and pharmacological recommendations for preventing and treating GC-induced osteoporosis.[89]

Place of the Elderly in the Recommendations

The 2015 Guidelines of the ACR and 2016 EULAR recommendations do not include recommendations regarding the elderly.[16,72] However, comorbidities and safety issues should be taken into account when therapeutic adjustments are required. Specific EULAR recommendations reaffirm the relevance of managing the higher cardiovascular disease risk, not only in patients with RA, but also in those with SA or PsA. The necessity of using NSAIDs and GCs sparingly has also been stressed,[90] but recommendations concerning GC use in elderly RA patients are lacking.[22]