Vela et al. Arthritis Research & Therapy (2020) 22:143 https://doi.org/10.1186/s13075-020-02231-x RESEARCH ARTICLE Open Access Influence of age on the occurrence of adverse events in rheumatic patients at the onset of biological treatment: data from the BIOBADASER III register Paloma Vela1,2, Carlos Sanchez-Piedra3, Carolina Perez-Garcia4, María C. Castro-Villegas5, Mercedes Freire6, Lourdes Mateo7, Cesar Díaz-Torné8, Cristina Bohorquez9, Juan M. Blanco-Madrigal10, Inmaculada Ros-Vilamajo11, Silvia Gómez2, Rocio Caño2, Fernando Sánchez-Alonso3, Federico Díaz-González3,12* and Juan J. Gómez-Reino13 Abstract Objectives: To assess whether age, at the beginning of biologic treatment, is associated with the time a first adverse event (AE) appears in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA). Methods: All patients in the BIOBADASER registry diagnosed with RA, AS, and PsA, and classified as young (< 25 years old), adult (25–64 years old), elderly (65–75 years old) or very elderly (> 75 years old) at start of biological treatment were included. Factors associated with the appearance of a first AE using adjusted incidence rate ratios (IRR) (Poisson regression) were analyzed. Survival to first AE was studied by Kaplan-Meier analysis and hazard ratios (HR) by Cox regression. Results: 2483 patients were included: 1126 RA, 680 PsA, and 677 AS. Age group stratification was as follows: 63 young, 2127 adults, 237 elderly, and 56 very elderly. Regression model revealed an increased probability of suffering a first AE at age 65 years or older [IRR elderly: 1.42 (CI95% 1.13–1.77)]. Other characteristics associated with AE were female gender, the use of DMARDs, including methotrexate, the presence of comorbidities, and the time of disease duration. Factors that had the greatest impact on survival over a first AE were age > 75 years [HR 1.50 (1.01–2.24)] and female gender [HR 1.42 (1.22–1.64)]. Conclusion: Age at the start of treatment and female gender are key factors associated with the appearance of a first AE with biologics. Other factors related to patient status and treatment were also associated with a first AE in rheumatic patients treated with biologics. Keywords: Rheumatoid arthritis, Ankylosing spondylitis, Psoriatic arthritis, Biologics, Elderly-onset rheumatoid arthritis * Correspondence: federico.diaz.gonzalez@gmail.com 3 Unidad de Investigación SER, Madrid, Spain 12 Departamento de Medicina Interna, Servicio de Reumatologia, Hospital Universitario de Canarias, Universidad de La Laguna, Calle Ofra s/n 38320, La Laguna, Santa Cruz de Tenerife, Spain Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Arthritis Research & Therapy (2020) 22:143 Page 2 of 9 Introduction is associated with the time the first AE (regardless of its Demographic trends are shaping the rapidly growing severity and outcome) appears in patients with RA, AS, population aged 65 years and older throughout Western or PsA. Other clinical factors, including gender and society [1]. This has enabled patients with chronic arth- those related to concomitant medications, were also ritis to reach advanced ages, as well as the appearance of evaluated. rheumatic diseases in more elderly individuals. With re- gard to rheumatic diseases, an increasing number of pa- Patients and methods tients are being diagnosed with elderly-onset rheumatoid This was a multicenter prospective study with a real- arthritis (EORA) [2]. In 2017, a retrospective study [3] world setting. Information was obtained from BIOBA- reported that the mean age of RA onset had significantly DASER, a national prospective registry of patients with increased over the previous decade, from 55.8 years in rheumatic diseases treated with biologic disease- 2002–2003 to 59.9 years in 2012–2013, with a corre- modifying antirheumatic drugs (bDMARDs), including sponding shift in peak age from 50–59 to 60–69 years biosimilars and targeted synthetic disease-modifying an- during that same time period. Although spondylarthro- tirheumatic drugs (tsDMARDs), either with approved or pathies are generally encountered in young patients, all off-label indications. BIOBADASER has been continu- of the spondyloarthritis subgroups are represented in the ously collecting patient data since 2000. Its primary ob- elderly [4]. Although previous epidemiological series re- jective is assessing the safety of both bDMARDs and ported a prevalence for late-onset ankylosing spondylitis tsDMARDs. The previous version of BIOBADASER was between 3 and 8% [5], the real prevalence of late-onset updated in December 2015 and is known as BIOBADA- spondyloarthritis remains little known. SER III [18]. With this update, an appraisal of the effect- Regarding clinical manifestations, previous studies iveness of these treatments was added as a secondary have found differences in EORA patients with respect to objective. The registry protocol and materials of BIOBA- young-onset rheumatoid arthritis subjects in terms of DASER III are available at http://biobadaser.ser.es. the disease’s aggressiveness [6] and associated comorbid- Briefly, all patients included in BIOBADASER are ities, as well as poorer physical function, although the followed-up prospectively. The information of each pa- treatment provided the EORA groups was generally less tient is added to the registry at least once a year for intensive [7]. Most of these studies were carried out in treatment effectiveness issues, as well as every time that Asiatic populations, with evidence on Caucasians being an AE or change in b/tsDMARDs treatment occurs. To more limited. The late-onset group (> 50 years) of anky- assess both consistency and quality, the full database is losing spondylitis (AS) patients have exhibited greater monitored online annually; additionally, a sample of pa- neck and peripheral arthritis involvement than their tient medical records are randomly selected and audited younger counterparts [8]. .Moreover, in psoriatic arth- annually in situ by a specialized monitor at all 28 partici- ritis (PsA) patients, elderly-onset has been linked to pating centers. more severe manifestations and worse outcomes than in younger individuals [9, 10]. The risks that biological therapies pose in older pa- Population tients have been previously evaluated. However, evidence For this analysis, all patients included in BIOBADASER remains scarce and mainly stems from clinical trials. In III with a diagnosis of either RA, PsA, or AS were se- such studies, the elderly population is often underrepre- lected and classified into four categories according to sented and usually only those with a few comorbidities age at the start of biologics treatment: young (< 25 years are selected, achieving at best 12–22% in RA study old), adults (25–64 years old), elderly (65–75 years old), groups [11], and only 5.3% and 1.4% in PsA and AS, re- and very elderly (> 75 years old). Data extraction was spectively [12]. Gradually more data on biologic therapy conducted in December 2018. The analysis of this study in the elderly population are becoming available, but includes data from 2000 to December 2018, and only experience remains limited and is almost exclusively those patients under active follow-up at the end of the focused on tumor necrosis factor (TNF)-inhibitors(i) study period were included. Signed informed consent [13–16]. In this context, real-world evidence studies are was obtained from all patients included in the BIOBA- needed to answer questions related to these older popu- DASER III registry, covering all subsequent analysis in- lations commonly excluded from clinical trials [17]. cluding the present study. Our hypothesis is that patient age at the beginning of This study was approved by the Ethics Committee biological therapy is a risk factor for the early onset of a (Hospital Clinic, Barcelona, Spain) and performed in ac- first adverse event (AE). Therefore, the aim of this work cordance with Good Pharmacoepidemiology Practice was to assess whether age at the beginning of the bio- Standards and with the principles of the Declaration of logical treatment (regardless of the initial biologic used) Helsinki. Vela et al. Arthritis Research & Therapy (2020) 22:143 Page 3 of 9 Outcome variables Factors related to the incidence of the first AE The primary objective of this study was to evaluate the We initially analyzed all patients independently of the impact of age on the appearance of AEs at the beginning diagnosis. Table 2 shows the increased probability of of biological treatments in patients with rheumatic dis- suffering a first AE in relation to age at the beginning of eases. AE was defined in BIOBADASER as any AE con- biological treatment [IRR for elderly, 1.42 (CI95% 1.13– sidered clinically relevant by the participating researcher. 1.77), and IRR for the very elderly, 1.89 (CI95%1.27– Those that required hospitalization or caused death were 2.81)], female gender [IRR 1.43 (CI95% 1.23–1.66)], the considered serious AEs. For the purpose of this analysis, use of MTX [IRR: 1.40 (CI95% 1.22–1.61)], and IRR for we evaluated every AE independently of its severity. The other DMARDs, 1.29 [CI95% 1.12–1.50], but not in rela- following data were collected: (1) patient data, including tion neither to the use of corticoids nor their initial dose gender, date of birth, diagnosis and date of diagnosis, co- in the adjusted regression models. Smoking habit was as- morbidities (Charlson index), and risk factors (smoking sociated with a higher incidence of a first AE [IRR for status); (2) data on treatment, duration of biologic treat- current and past smokers, 1.31 (1.12–1.52)]. Comorbidi- ment, types of biologics, and concomitant DMARD ties, as assessed by the Charlson Index, also significantly treatments; and (3) data on AE, including date of increased the likelihood of a first AE in the same ad- occurrence. justed model [IRR, 1.14 (CI95% 1.07–1.22)]. Supplemen- tary Table 1 shows the interaction effect of age and gender. Data demonstrate that the effect of age on the Statistical analysis appearance of AEs at the start of biological treatment Proportions, means, and standard deviations were used occurs independently of gender. to describe the population. A Poisson regression model Table 3 shows the same analyses stratified by diagno- was carried out to explore the effects of, and other fac- sis. Elderly patients exhibited an increased probability of tors associated with, the appearance of a first AE age at suffering a first AE if they were diagnosed with RA and the beginning of biological therapy. Crude and adjusted PsA, but not AS. In RA patients, comorbidities [IRR 1.08 incidence rate ratios (IRRs) were calculated. Survival to (CI95% 1.00–1.17)] and a former smoking habit [IRR first AE was studied by Cox regression models and 1.28 (CI95% 1.05–1.57)] were associated with higher Kaplan-Meier analysis. As both age and gender were as- probabilities of suffering a first AE. In PsA patients, fe- sociated with the risk of a first AE, we introduced an male gender [IRR 1.60 (CI95% 1.26–2.04)], as well as the interaction term (age-sex) in the model. All analyses use of MTX [IRR 1.31 (CI95% 1.01–1.68)], other were performed using Stata version 13.1 (Stata Corp., DMARDs [IRR 1.43 (CI95% 1.09–1.88)], and cortico- College Station, TX 2013). steroids [IRR 1.48 (CI95% 1.13–1.93)], was associated with a first AE. In AS, female gender [IRR 1.42 (CI95% 1.09–1.85)], the use of MTX [IRR 1.56 Results (CI95% 1.13–2.14)], the Charlson Index score [IRR A total of 2483 patients were included in this study: 1.28 (CI95% 1.06–1.54)], and disease duration [IRR 1126 (45.34%) RA, 680 (27.39%) PsA, and 677 (27.27%) 1.02 (CI95% 1.01–1.03)] were associated with the ap- AS. Baseline characteristics of patients by age group at pearance of a first AE. onset of biological therapy are summarized in Table 1. A breakdown of the groups by age is as follows: 63 (2.53%) patients were young, 2127 (85.66%) adults, 237 (9.54%) Risk factors at the start of biological treatment on the elderly, and 56 (2.25%) very elderly. The percentage of time to a first AE women was greater in patients older than 65 years. Time The time period until the appearance of a first AE was of disease duration increased with age, while duration of significantly longer in younger patients than in the adult, biologic treatment decreased. Comorbidities assessed by elderly, and very elderly groups (Fig. 1) (p < 0.001, log- the Charlson index increased with age, while smoking rank test). Cox regression analysis (Table 4) shows that decreased (23.81% young, 30.32% adults, 27.00% elderly, risk factors for the appearance of the first AE were age and 12.50% very elderly). Methotrexate (MTX) was used over 65 years (HR elderly 1.21, CI95% 0.97–1.52; HR similarly across all age groups (53.69% in the total sam- very elderly 1.50, CI95% 1.01–2.24), female gender (HR ple), although treatment with corticosteroids increased 1.42, CI95% 1.22–1.64), the use of MTX (HR 1.21, with age (young 27.78%, adults 46.51%, elderly 64.18%, CI95% 1.05–1.39), the presence of comorbidities (HR and very elderly 71.74%). When AE’s were analyzed, a 1.13, CI95% 1.06–1.21), and disease duration (HR 1.01, tendency to increase their percentage with age was ob- CI95% 1.00–1.02). In our study, no significant differ- served, both in the total and in the severe ones, but ences were observed among the different rheumatic dis- without reaching statistical significance. eases studied in terms of the risk of suffering a first AE. Vela et al. Arthritis Research & Therapy (2020) 22:143 Page 4 of 9 Table 1 Characteristics of patients and first AE reported according to age group at onset of biological therapy Variables Young Adult Elderly Very Elderly p N = 2483 63 2127 237 56 Age, mean (SD) in years 21.48 (4.48) 47.91 (9.98) 69.12 (2.87) 78.81 (3.10) Female gender (%) 25 (39.68) 1163 (54.68) 171 (72.159) 42 (75.09) < 0.001 Disease duration, mean (SD) in years 2.72 (3.39) 7.28 (7.68) 9.46 (9.40) 8.19 (8.95) < 0.001 Duration of biologic treatment, mean (SD) in years 3.12 (3.409) 2.60 (3.14) 1.79 (2.18) 1.57 (1.95) < 0.001 Diagnosis, n (%) RA, n = 1126 13 (1.15) 903 (80.20) 161 (14.30) 49 (4.35) < 0.001 PsA, n = 680 35 (5.15) 610 (89.71) 32 (4.71) 3 (0.44) AS, n = 677 15 (2.22) 614 (90.69) 44 (6.50) 4 (0.59) Comorbidities Charlson Index, mean (SD) 1.02 (0.13) 1.25 (0.68) 1.81 (1.49) 2.07 (1.41) < 0.001 Tobacco: smokers/past smokers, n (%) 15 (23.81) 645 (30.32) 64 (27.00) 7 (12.50) 0.047 Concomitant immunosuppressive treatment, n (%) of use MTX 23 (41.8) 943 (53.61) 106 (55.79) 27 (60.00) 0.243 Corticosteroids 15 (27.78) 806 (46.51) 129 (64.18) 33 (71.74) < 0.001 Initial corticoids dose (mg/day) 15.55 (16.26) 8.29 (7.24) 8.03 (5.85) 8.03 (6.37) 0.011 Other 8 (12.70) 627 (29.48) 83 (35.02) 23 (41.07) 0.002 First AE (Total), n (%) 33 (52.4) 1227 (57.7) 147 (62.0) 37 (66.1) Infections 9 (27.27) 391 (31.87) 50 (34.01) 11 (29.73) 0.789 Traumatic injuries 2 (6.06) 104 (8.48) 14 (9.52) 3 (8.11) Neoplasms 0 (0.00) 28 (2.28) 6 (4.08) 1 (2.70) Skin disorders 5 (15.15) 131 (10.68) 15 (10.20) 1 (2.70) Others 17 (51.52) 573 (46.70) 62 (42.18) 21 (56.76) First severe AE, n (%) 4 (6.3) 138 (6.5) 36 (15.2) 11 (19.6) Infections 1 (25.00) 45 (32.61) 13 (36.11) 1 (9.09) 0.052 Traumatic injuries 0 (0.00) 9 (6.52) 2 (5.56) 1 (9.09) Neoplasms 0 (0.00) 17 (12.32) 3.8 (8.33) 0 (0.00) Skin disorders 0 (0.00) 0 (0.00) 0 (0.00) 1 (9.09) Others 3 (75.00) 67 (48.55) 18 (50.00) 8 (72.73) No AE n (%) 30 (47.6) 900 (42.3) 90 (38.0) 19 (33.9) AS ankylosing spondylitis, MTX methotrexate, PsA psoriatic arthritis, RA rheumatoid arthritis, TNF-i tumor necrosis factor inhibitor Discussion death) in older populations [12, 13, 19, 20], although this The most important findings of this study can be sum- risk appears to be related to age itself. marized as follows: (1) age at the start of biologic treat- Exactly how “elderly” is defined remains an important ment is the most important risk factor for the issue. Per convention, a person aged 65 years or more is appearance of a first AE in RA, PsA, and EA patients often referred to as “elderly” [21]. However, elderly- and (2) female gender, the concomitant use of MTX, onset rheumatoid arthritis (EORA) is defined as RA with and the presence of comorbidities are also factors that an onset at age 60 years or over. Some groups have used increase said risk. the term “very old” to refer to people older than 75 or Our study consistently shows that the incidence of the 80 years. It does make sense to consider separately those first AE in rheumatic patients treated with biologics in- older than 75 years, taking into account that differences creases with age. Previous studies have shown the influ- in both efficacy and safety responses have been found ence of age on the risk of AEs in patients treated with with older populations [22]. Thus, we decided to analyze biologics. In addition, several studies are in agreement independently people age 75 years or more (“very eld- on the higher risk of serious infections (requiring erly”). Our results showed a progressive increase in the hospitalization, intravenous antibiotics, or resulting in probability of having a first AE in relation to age at the Vela et al. Arthritis Research & Therapy (2020) 22:143 Page 5 of 9 Table 2 IRR of time to first AE. Poisson regression model crude and adjusted Variables Crude IRR (CI95%) p Adjusted IRR (CI95%) p Age (ref. adult)* Young 0.76 (0.54–1.09) 0.140 1.00 (0.66–1.53) 0.985 Elderly 1.61 (1.36–1.91) < 0.001 1.42 (1.13–1.77) 0.002 Very elderly 2.01 (1.45–2.79) < 0.001 1.89 (1.27–2.81) 0.002 Female gender 1.33 (1.20–1.49) < 0.001 1.43 (1.23–1.66) < 0.001 Diagnosis (ref. RA) AS 0.80 (0.70–0.91) 0.001 1.10 (0.91–1.33) 0.336 PsA 0.96 (0.84–1.09) 0.512 1.12 (0.94–1.33) 0.208 Comorbidities Charlson Index 1.15 (1.09–1.22) < 0.001 1.14 (1.07–1.22) < 0.001 Smoking (ref. No) Smoker/past smoker 1.25 (1.11–1.41) < 0.001 1.31 (1.12–1.52) 0.001 Treatments Corticosteroids (ref. No) 1.31 (1.17–1.46) < 0.001 1.1 (0.96–1.26) 0.192 Initial mean dose corticosteroids 1.00 (0.99–1.01) 0.842 0.99 (0.97–1.00) 0.100 MTX (ref. No) 1.41 (1.26–1.58) < 0.001 1.40 (1.22–1.61) < 0.001 Other DMARDs (ref. No) 1.17 (1.05–1.31) 0.006 1.29 (1.12–1.50) 0.001 Time of disease duration& 1.01 (1.00–1.01) 0.054 1.14 (1.07–1.22) < 0.001 AS ankylosing spondylitis, DMARDs disease-modifying antirheumatic drugs, IRR incidence rate ratio, MTX methotrexate, PsA psoriatic arthritis, RA rheumatoid arthritis, TNFi tumor necrosis factor inhibitor *Age at the beginning of biological treatment onset of biological treatment. Variability between studies time of the AE, information that could complement in age group definition complicates such comparisons, a these findings. Overall, in terms of pathologies, no problem that affects other fields in addition to rheuma- significant differences in the probability of a first AE tology [23]. Our data also show that female gender is as- were found, a finding in concordance with the previ- sociated with higher risk of a first AE in patients treated ous report [29]. with biologics, particularly in PsA. Some previous stud- The current study has some limitations. First of all, ies have found similar findings in drug retention rates in most of our population (85%) were classified into the patients with PsA and AS [24]. However, the interaction “adult” group, which reflects the prevalence typical of model shows that gender does not seem to influence the this disease type, predominantly one afflicting those in effect of age at starting biologics on AEs. middle age [30]. Moreover, the “adult” group naturally Additionally, our study found that another factor con- corresponds to a higher age-range bracket. For all these tributing to the development of a first AE was the use of reasons, we decided to classify patients according to concomitant therapy, especially MTX. MTX’s effect was their age at the start of biological therapy. Comparisons observed in patients generally and when stratified by between studies in elderly patients are difficult due to a diagnosis. Previous studies on elderly RA patients have lack of consensus on defining age groups. Although reported findings consistent with our own [19, 20, 22, EORA is usually defined as disease beginning at age 60 23, 25], although some linked MTX toxicity mainly to years or older, some authors classify as “elderly” those renal function impairment rather than age itself [26]. As patients aged 65 years or older, differentiating as “very we do not have any renal function data, we cannot cor- old” those older than 75 years [21, 31]. Second, we have roborate this observation. We found an increased use of evaluated those factors related to the appearance of a corticosteroids with age, in agreement with previous first AE, independently of the type of AE or their attend- studies [19, 27]. Although corticosteroid exposure ap- ant consequences. Most published studies have analyzed pears to be an important predictor of infection [22, 28], the influence of age on treatment discontinuation or on in our study, neither the use of these compounds nor the onset of serious AEs. Our study sought to study fac- their initial dose did not seem to contribute to an initial tors associated with the appearance of a first AE. How- AE. It is important to note that BIOBADASER does not ever, one must bear in mind that the aging process is record the dose of glucocorticoids administered at the not experienced uniformly across the general population Table 3 IRR of time to first AE stratified by diagnostic group. Poisson regression model, crude, and adjusted Vela et al. Arthritis Research & Therapy Variable RA PsA AS Crude IRR (CI95%) p Adjusted IRR (CI95%) p Crude IRR (CI95%) p Adjusted IRR (CI95%) p Crude IRR (CI95%) p Adjusted IRR (CI95%) p Age (ref. adults)* Young 1.16 (0.62–2.17) 0.639 1.20 (0.62–2.33) 0.585 0.47 (0.19–1.13) 0.091 0.49 (0.18–1.31) 0.153 0.85 (0.52–1.39) 0.53 1.13 (0.67–1.90) 0.65 Elderly 1.59 (1.30–1.95) < 0.001 1.55 (1.23–1.95) < 0.001 1.60 (1.08–2.36) 0.019 1.25 (0.89–1.97) 0.336 1.36 (0.73–2.56) 0.336 1.34 (0.63–2.86) 0.446 (2020) 22:143 Very Elderly 1.77 (1.24–2.52) 0.002 1.76 (1.18–2.61) 0.005 4.35 (1.40–13.57) 0.011 4.40 (1.30–14.87) 0.017 5.94 (1.48–23.84) 0.012 2.86 (0.65–12.59) 0.165 Women 1.00 (0.83–1.20) 0.99 1.14 (0.93–1.41) 0.209 1.72 (1.40–2.11) < 0.001 1.60 (1.26–2.04) < 0.001 1.35 (1.07–1.70) 0.012 1.42 (1.09–1.85) 0.01 Treatments Corticosteroids 1.01 (0.86–1.18) 0.913 1.73 (1.37–2.18) < 0.001 1.48 (1.13–1.93) 0.004 1.59 (1.17–2.16) 0.003 1.35 (0.95–1.91) 0.098 MTX 1.26 (1.07–1.47) 0.004 1.25 (1.07–1.47) 0.006 1.34 (1.07–1.69) 0.012 1.31 (1.01–1.68) 0.041 1.78 (1.36–2.31) < 0.001 1.56 (1.13–2.14) 0.006 Other 1.08 (0.93–1.25) 0.325 1.37 (1.09–1.72) 0.008 1.43 (1.09–1.88) 0.01 1.02 (0.76–1.36) 0.897 Smoking (ref. No) Smoker/past 1.29 (1.09–1.53) 0.004 1.28 (1.05–1.57) 0.015 1.36 (1.07–1.73) 0.012 1.09 (0.81–1.46) 0.578 1.26 (1.01–1.58) 0.042 1.18 (0.90–1.54) 0.234 smoker Comorbidities Charlson Index 1.12 (1.05–1.20) 0.001 1.08 (1.00–1.17) 0.048 1.13 (1.00–1.29) 0.056 1.09 (0.93–1.29) 0.293 1.26 (1.07–1.47) 0.005 1.28 (1.06–1.54) 0.01 & Time 1.00 (0.99–1.01) 0.818 1.01 (0.99–1.03) 0.399 1.01 (1.00–1.03) 0.008 1.02 (1.01–1.03) 0.004 *Age at the beginning of biological treatment & Time of disease duration AS ankylosing spondylitis, DMARDs disease-modifying antirheumatic drugs, IRR incidence rate ratio, MTX methotrexate, PsA psoriatic arthritis, RA rheumatoid arthritis, TNFi tumor necrosis factor inhibitor Page 6 of 9 Vela et al. Arthritis Research & Therapy (2020) 22:143 Page 7 of 9 Fig. 1 Survival analysis. Time to first AE. Kaplan-Meier graph. AE, adverse event. LogrRank test, p < 0.001 due to differences in genetics, lifestyle, and overall health increased risk of poor health outcomes, including falls, [32]. In order to establish risk groups, the optimum clas- disability incidents, hospitalizations, and increased mor- sification parameter to use instead of chronological age tality [33]. Although tools designed to measure frailty do would most likely be “frailty”, which is defined as a clin- exist, they were not included in BIOBADASER and ical syndrome in older adults, and one which carries an therefore we could not incorporate them into the present study. Table 4 Cox regression analysis Variables Hazard ratio (CI95%) p Age (ref. adults) Conclusions Young 0.92 (0.60–1.40) 0.692 Age at starting biological therapy is a key factor that Elderly 1.21 (0.97–1.52) 0.089 seems to explain the appearance of a first AE in rheum- Very Elderly 1.50 (1.01–2.24) 0.046 atic patients. Other characteristics and clinical vari- Female gender 1.42 (1.22–1.64) < 0.001 ables—such as female gender, the concomitant use of MTX, and the presence of comorbidities—are also fac- Diagnosis (ref. RA) tors that increase the risk of a first AE in this group of AS 0.93 (0.76–1.12) 0.432 patients. PsA 0.96 (0.81–1.14) 0.668 Comorbidities Charlson index 1.13 (1.06–1.21) < 0.001 Supplementary information Supplementary information accompanies this paper at https://doi.org/10. Smoking (ref. No) 1186/s13075-020-02231-x. Smoker/past smoker 1.16 (0.99–1.35) 0.059 Additional file 1: Table 1S. Poisson regression model including the Treatments study of interaction sex-age. IRRs Adjusted. Corticosteroids 1.04 (0.85–1.27) 0.699 Corticosteroid dose 0.99 (0.97–1.00) 0.140 MTX 1.21 (1.05–1.39) 0.008 Abbreviations Other DMARDs 1.10 (0.95–1.28) 0.182 AE: Adverse event; AS: Ankylosing spondylitis; bDMARDs: Biologic disease- modifying antirheumatic drugs; CI: Confidence interval; EORA: Elderly-onset Disease duration 1.01 (1.00–1.02) 0.007 rheumatoid arthritis; HR: Hazard ratios; IRR: Incidence rate ratios; AS ankylosing spondylitis, CI95% confidence interval 95%, DMARDs disease- MTX: Methotrexate; PsA: Psoriatic arthritis; RA: Rheumatoid arthritis; modifying antirheumatic drugs, HR hazard ratios, MTX Methotrexate, PsA tsDMARDs: Targeted synthetic disease-modifying antirheumatic drugs; psoriatic arthritis, RA rheumatoid arthritis TNFi: Tumor necrosis factor inhibitors Vela et al. Arthritis Research & Therapy (2020) 22:143 Page 8 of 9 Acknowledgements 6. Murata K, Ito H, Hashimoto M, Nishitani K, Murakami K, Tanaka M, We gratefully thank all the researchers of the BIOBADASER group for their Yamamoto W, Mimori T, Matsuda S. Elderly onset of early rheumatoid collaboration. We also thank Jesus T. Sanchez-Costa and Nuria Montero for arthritis is a risk factor for bone erosions, refractory to treatment: KURAMA their help as CRAs in BIOBADASER. cohort. Int J Rheum Dis. 2019;22(6):1084–93. 7. Tan TC, Gao X, Thong BYH, Leong KP, Lian TY, Law WG, Kong KO, Howe HS, Authors’ contributions Chng HH, Koh ET. Comparison of elderly-and young-onset rheumatoid PV designed the study. CS-P and FS-A contributed to data management and arthritis in an Asian cohort. Int J Rheum Dis. 2017;20(6):737–45. statistical analysis. PV, CS-P, and FD-G draft the publication, and all authors 8. Montilla C, Del Pino-Montes J, Collantes-Estevez E, Font P, Zarco P, Mulero J, were involved in critically revising the article. All authors have contributed to Gratacós J, Rodríguez C, Juanola X, Fernández-Sueiro JL. Clinical features of the discussion and interpretation of the results. The final version of the late-onset ankylosing spondylitis: comparison with early-onset disease. J manuscript was read and approved by all authors. Rheumatol. 2012;39(5):1008–12. 9. Toussirot E, Wendling D. Late-onset ankylosing spondylitis and related Funding spondylarthropathies. Drugs Aging. 2005;22(6):451–69. BIOBADASER is supported by the Spanish Agency for Medicine and Health 10. Toussirot É. Late-onset ankylosing spondylitis and spondylarthritis. Drugs Products (AEMPS), Biogen, Bristol-Myers Squibb (BMS), Celltrion Healthcare, Aging. 2010;27(7):523–31. Lilly, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, and Samsung 11. Bathon JM, Fleischmann RM, Van der Heijde D, Tesser JR, Peloso PM, Chon Bioepis. Y, White B. Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. 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