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The aim of this study was to evaluate structural damage and physical disability in patients with elderly-onset RA (EORA) who were treated in clinical practice with a therapeutic strategy targeting low disease activity (LDA).Methods. Data from 151 MTX-naive patients (mean age 74.9 years) with EORA from a prospective, monocentric registry were analysed. Treatment was adjusted every 3 months targeting LDA 28-joint DAS using ESR (DAS28-ESR). , IntroductionRA is a chronic inflammatory disease causing joint destruction and functional disability.
Although the disease is commonly diagnosed between the ages of 30 and 50, the mean age at diagnosis has increased recently in an ageing society. Previous prospective studies have shown that elderly-onset RA (EORA) patients have a prognosis as poor as that for patients with younger-onset RA in terms of radiographic progression and physical disability ,. In addition, EORA patients tend to have more co-morbidities such as cardiovascular disease. However, data on the outcome of aggressive treatments, including biologics, for patients with EORA are limited and available evidence from randomized controlled trials (RCTs) originate from post hoc analyses studying the efficacy of TNF inhibitors (TNFis) ,. Since it is difficult to enrol elderly patients, who are more complex and variable than non-elderly patients, for conventional RCTs , observational studies to establish the optimal management of EORA are warranted.Elderly RA, EORA and younger-onset RA share some but not all clinical features ,. In patients with EORA and younger-onset RA, a prospective study found that high disease activity (HDA) at baseline and being RF positive and HLA-DR4 positive were associated with progression of joint destruction. Post hoc analyses of RCTs showed TNFi with or without MTX was more effective in improving disease activity and physical function and reducing structural damage for elderly RA patients than MTX monotherapy ,.
However, the efficacy of TNFi/MTX therapy demonstrated by RCTs is likely to be better than the effectiveness observed in clinical practice due to strict eligibility criteria. Two large prospective cohort studies suggested that it was more challenging to control disease activity and normalize physical function with TNFi in established long-standing elderly RA populations compared with younger RA populations ,.
However, these studies did not address the case of patients with EORA.Targeted therapy is the consensus strategy for patients with RA and clinical remission is a realistic goal. On the other hand, the recommendation showed that the level of achievement of this target may be influenced by co-morbidities, patient factors and drug-related risks. Because co-morbidities are more common among elderly patients , , and both increasing age and the use of TNFis are significantly associated with an increased risk of serious infections , it is unclear whether the therapeutic strategy targeting low disease activity (LDA) is applicable to the EORA population and can lead to good outcome in clinical practice.In this study we report the 1 year outcomes of our prospective cohort for MTX-naive EORA patients. The purpose of this study was to evaluate the structural damage and physical disability of enrolled patients who were treated with a therapeutic strategy targeting LDA.
Patients and methods PatientsThe Choju registry is a prospective, monocentric registry administered by the Department of Medicine and Rheumatology of the Tokyo Metropolitan Geriatric Hospital. Choju is a Japanese word meaning long life. The registry and this study were approved by the ethics committee of Tokyo Metropolitan Geriatric Hospital and informed consent was obtained from all patients. The inclusion criteria are those patients (i) meeting the 1987 ACR criteria for RA, (ii) ≥60 years old and able and willing to provide written informed consent in accordance with the Declaration of Helsinki, (iii) having a 28-joint DAS using ESR (DAS28-ESR) of ≥3.2 and (iv) starting treatment with biologics or non-biologic DMARDs (nbDMARDs) at the time of study entry.
MTX-naive patients were selected from the Choju registry for this study as a nested cohort, the Choju registry of RA treated with non-biologic DMARDs and biologics in elderly patients in Japan (CRANE). Those patients withdrawing consent to join the study were excluded.
A total of 151 MTX-naive patients with EORA were recruited between October 2008 and September 2012. TreatmentsTreatments were intensified if a patient had insufficient response according to the discretion of an attending rheumatologist at week 12 or did not achieve LDA (DAS28-ESR 30 ml/min but 0.7 indicates a reasonable ability to discriminate between patients with and without CRRP.
All analytical procedures were performed using SPSS version 20 (IBM, Armonk, NY, USA). All reported P-values were two-tailed and the level of significance was P 5.1) in 82.1% of the patients. During 24–52 weeks, four patients withdrew because of serious AEs and two declined follow-up. Age, mean ( s.
D.), years74.9 (6.8)Female sex,%72.8Body weight, mean ( s. D.), kg51.6 (10.3)Ccr, mean ( s. D.) (determined by the Cockcroft–Gault formula), ml/min64.7 (21.0)Ccr. Age, mean ( s.
D.), years74.9 (6.8)Female sex,%72.8Body weight, mean ( s. D.), kg51.6 (10.3)Ccr, mean ( s. D.) (determined by the Cockcroft–Gault formula), ml/min64.7 (21.0)Ccr. Age, mean ( s. D.), years74.9 (6.8)Female sex,%72.8Body weight, mean ( s.
D.), kg51.6 (10.3)Ccr, mean ( s. D.) (determined by the Cockcroft–Gault formula), ml/min64.7 (21.0)Ccr.
Age, mean ( s. D.), years74.9 (6.8)Female sex,%72.8Body weight, mean ( s. D.), kg51.6 (10.3)Ccr, mean ( s. D.) (determined by the Cockcroft–Gault formula), ml/min64.7 (21.0)Ccr. TherapyAt week 0, 110 of 151 patients received an average dose of 5.8 mg/week of MTX, 17 tacrolimus, 20 salazosulphapyridine or bucillamine, 3 etanercept, 1 tocilizumab and 50 PSL mean dose 6.4 mg/day ( s. Adherence to the treatment protocol was observed in 83.4% of the 151 patients at week 24 and in 75.5% at week 52.
During the 52 weeks, 117 of the 151 patients received MTX, and the dosage of MTX was increased to 8.9 mg/week ( s. 2.6) 0.17 mg/kg/week ( s.
Forty-seven (40.2%) of the 117 patients had renal dysfunction mean Ccr 46.8 ( s. 10.2), 52 (44.4%) had MTX-associated AEs and 27 (23.1%) achieved LDA with a low dose of MTX. There were no patients taking the maximum approved dosage of MTX (i.e.
At week 52, 45 of 145 patients received TNFi, 2 tocilizumab and 46 PSL mean dose 3.6 mg/day ( s. Actual medication use and radiological progression during the 52 weeks of follow-upTreatment of patients who started ( A) MTX at week 0, ( B) tacrolimus and ( C) salazosulphapyridine or bucillamine. ( D) Cumulative probability plot of change in mTSS. ( E) Area-proportional Venn diagram showing the interrelationships between disease activity status (left diagram: LDA; right diagram: clinical remission).
( F) Association of CRRP with cumulative disease activity. C-statistic of the AUC of the DAS28 during the first 12 weeks (model 1), 24 weeks (model 2) and 36 weeks (model 3). A high C-statistic corresponds to a high prognostic ability. ADA: adalimumab; AUC: area under the curve; BUC: bucillamine; CRRP: clinically relevant radiographic progression; DAS28: 28-joint DAS; ETN: etanercept; IFX: infliximab; LDA: low disease activity; mTSS: modified total Sharp score; PSL: prednisolone; RRP: rapid radiographic progression; SASP: salazosulfapyridine; TAC: tacrolimus; TCZ: tocilizumab. Actual medication use and radiological progression during the 52 weeks of follow-upTreatment of patients who started ( A) MTX at week 0, ( B) tacrolimus and ( C) salazosulphapyridine or bucillamine.
( D) Cumulative probability plot of change in mTSS. ( E) Area-proportional Venn diagram showing the interrelationships between disease activity status (left diagram: LDA; right diagram: clinical remission).
( F) Association of CRRP with cumulative disease activity. C-statistic of the AUC of the DAS28 during the first 12 weeks (model 1), 24 weeks (model 2) and 36 weeks (model 3). A high C-statistic corresponds to a high prognostic ability. ADA: adalimumab; AUC: area under the curve; BUC: bucillamine; CRRP: clinically relevant radiographic progression; DAS28: 28-joint DAS; ETN: etanercept; IFX: infliximab; LDA: low disease activity; mTSS: modified total Sharp score; PSL: prednisolone; RRP: rapid radiographic progression; SASP: salazosulfapyridine; TAC: tacrolimus; TCZ: tocilizumab. Clinical responseAt week 12, 101 of 151 patients had a moderate or good European League Against Rheumatism (EULAR) response, but medication was changed in 4 of the 101 patients.
In 25 of the 50 EULAR non-responder patients at week 12, treatment was not intensified due to serious AEs (8 patients) and patient-related factors (17 patients) such as apprehensiveness about adding a TNFi to MTX. At week 24, 50 (33.1%) of 151 patients achieved the predefined goal of LDA and 17.2% achieved clinical remission (DAS28-ESR.Patients with PSL ( n = 61).Patients without PSL ( n = 90).P-value.Age, mean ( s.
D.), years77.2 (6.5)73.3 (6.5)0.5,%78.774.40.422HAQ-DI at week 0, mean ( s. D.)1.43 (0.91)1.02 (0.76)0.006Chronic lung disease,%26.223.30.685Diabetes mellitus,%14.728.90.043Ccr.Patients with PSL ( n = 61).Patients without PSL ( n = 90).P-value.Age, mean ( s. D.), years77.2 (6.5)73.3 (6.5)0.5,%78.774.40.422HAQ-DI at week 0, mean ( s. D.)1.43 (0.91)1.02 (0.76)0.006Chronic lung disease,%26.223.30.685Diabetes mellitus,%14.728.90.043Ccr.Patients with PSL ( n = 61).Patients without PSL ( n = 90).P-value.Age, mean ( s. D.), years77.2 (6.5)73.3 (6.5)0.5,%78.774.40.422HAQ-DI at week 0, mean ( s.
D.)1.43 (0.91)1.02 (0.76)0.006Chronic lung disease,%26.223.30.685Diabetes mellitus,%14.728.90.043Ccr.Patients with PSL ( n = 61).Patients without PSL ( n = 90).P-value.Age, mean ( s. D.), years77.2 (6.5)73.3 (6.5)0.5,%78.774.40.422HAQ-DI at week 0, mean ( s. D.)1.43 (0.91)1.02 (0.76)0.006Chronic lung disease,%26.223.30.685Diabetes mellitus,%14.728.90.043Ccr. Predictors of CRRP in patients with EORAOf the 145 patients who completed the 52-week follow-up, CRRP was observed in 57 (39.3%) and rapid radiographic progression (ΔmTSS/year ≥5.0) in 38 (26.2%) (D). Patients with CRRP had HDA and more radiological damage at baseline and were more often anti-CCP positive. The frequency of EULAR non-responders at week 12 and patients who did not achieve LDA at week 24 was significantly higher in the patients with CRRP.
Multivariate logistic regression models showed that these were independent risk factors for CRRP. Concomitant PSL therapy and non-adherence to the treatment protocol were not associated with CRRP.Patients with CRRP ( n = 57).Patients without CRRP ( n = 88).P-value.Age, mean ( s. D.), years74.9 (6.4)74.8 (7.0)0.964Gender, female,%75.471.60.610Symptom duration, median (IQR), months9.0 (4.8–30)6.0 (2.4–11.4)0.007DAS28-ESR at week 0, mean ( s.
D.)6.50 (1.11)5.99 (1.26)0.014CRP at week 0, median (IQR), mg/dl2.6 (0.9–4.4)2.6 (0.6–5.5)0.865Positive anti-CCP antibody,%82.148.90.5,%89.572.70.015Erosion score at week 0 ≥2,%75.445.5.Patients with CRRP ( n = 57).Patients without CRRP ( n = 88).P-value.Age, mean ( s. D.), years74.9 (6.4)74.8 (7.0)0.964Gender, female,%75.471.60.610Symptom duration, median (IQR), months9.0 (4.8–30)6.0 (2.4–11.4)0.007DAS28-ESR at week 0, mean ( s. D.)6.50 (1.11)5.99 (1.26)0.014CRP at week 0, median (IQR), mg/dl2.6 (0.9–4.4)2.6 (0.6–5.5)0.865Positive anti-CCP antibody,%82.148.90.5,%89.572.70.015Erosion score at week 0 ≥2,%75.445.5.Patients with CRRP ( n = 57).Patients without CRRP ( n = 88).P-value.Age, mean ( s. D.), years74.9 (6.4)74.8 (7.0)0.964Gender, female,%75.471.60.610Symptom duration, median (IQR), months9.0 (4.8–30)6.0 (2.4–11.4)0.007DAS28-ESR at week 0, mean ( s. D.)6.50 (1.11)5.99 (1.26)0.014CRP at week 0, median (IQR), mg/dl2.6 (0.9–4.4)2.6 (0.6–5.5)0.865Positive anti-CCP antibody,%82.148.90.5,%89.572.70.015Erosion score at week 0 ≥2,%75.445.5.Patients with CRRP ( n = 57).Patients without CRRP ( n = 88).P-value.Age, mean ( s. D.), years74.9 (6.4)74.8 (7.0)0.964Gender, female,%75.471.60.610Symptom duration, median (IQR), months9.0 (4.8–30)6.0 (2.4–11.4)0.007DAS28-ESR at week 0, mean ( s. D.)6.50 (1.11)5.99 (1.26)0.014CRP at week 0, median (IQR), mg/dl2.6 (0.9–4.4)2.6 (0.6–5.5)0.865Positive anti-CCP antibody,%82.148.90.5,%89.572.70.015Erosion score at week 0 ≥2,%75.445.5.
Association of CRRP with cumulative disease activityWe assessed the association of CRRP with cumulative disease activity between weeks 0 and 12 (Model 1), 0 and 24 (Model 2) or 0 and 36 (Model 3) using logistic regression models with covariates of age, gender, anti-CCP antibody, baseline HAQ-DI, baseline erosion score ≥2 and AUC of the DAS28-ESR. We calculated the C-statistic of each model to evaluate how well these three models fit the data for CRRP. The C-statistic of the AUC of the DAS28 during the first 12 weeks was comparable to that for the first 24 or 36 weeks (F).
AEsSerious infections were reported in 19 patients ; all were resolved by treatment and 16 of the 19 patients could continue the same treatment after the infectious AEs. Eleven of 19 serious infection cases received a median dose of 8 mg/day of PSL interquartile range (IQR) 5–10 mg/day, 17 received MTX mean dose 8.2 mg/week ( s. 2.1) and 7 received biologics.
All seven patients with PCP did not receive prophylaxis; five patients treated with MTX monotherapy had two risk factors and two treated with MTX/infliximab or MTX/etanercept had no risk factors except age. There were no cases of tuberculosis or reactivation of HBV. All five patients with extra-articular manifestations had HDA when ILD developed; 0.5–1 mg/kg/day of PSL was administered and four patients recovered, but one died of exacerbation of ILD at week 28.
Vasculitis was not found. Malignancy was reported in three patients receiving MTX; two cases of prostate cancer and one of oesophageal cancer. Cardiac diseases, including angina pectoris, variant angina pectoris and atrial flutter, were reported in three patients.
One patient with RA and aortic aneurysm died suddenly at week 26. DiscussionThis is the first study to assess the effectiveness and safety of a targeted treatment intensification strategy for patients with EORA.
Our results show that achieving LDA, structural remission and functional remission are realistic goals in clinical practice for EORA patients treated with a therapeutic strategy targeting LDA. We also demonstrated that about one-third of the patients developed CRRP and that the treatment response at week 12 and the total burden of disease activity during the first 12 weeks after treatment initiation were reliable predictors of joint destruction at 1 year.This study revealed that the baseline clinical factors associated with the development of joint destruction in the CRANE cohort were anti-CCP antibodies, baseline disease activity and baseline erosion score. These findings are in overall agreement with previous reports of predictors for joint destruction.
The most important finding in our study was that EULAR no response at week 12 was strongly associated with CRRP at 1 year in EORA patients treated by the targeted therapeutic strategy. These data are consistent with the ASPIRE trial results in patients receiving MTX monotherapy. RCTs from Japan and Western countries have shown that treatment with TNFi/MTX is significantly more beneficial than treatment with MTX alone, as measured by radiological findings at week 24 in patients with early active RA. Rapid improvement of disease activity by treatment with biologics reduced the risk of joint destruction in patients with poor prognostic features ,. Overall, it appears that persistently elevated disease activity and delay in treatment intensification are related to increased progression of joint damage in both RA and EORA.In general, elderly patients have reduced reversibility of functional impairment due to age-related factors or co-morbidities; these factors can affect the physical function of patients with EORA ,.
However, post hoc analysis of clinical trials and a cohort study showed that physical disability of elderly patients improved to levels similar to non-elderly patients during treatment. In the CRANE cohort, rates of co-morbidity were higher than those in registries of the general RA population in Japan and slightly higher than those in registries of the elderly RA population in Western countries ,. About one-fifth of all patients in the CRANE cohort experienced serious AEs during 1 year of treatment. Nevertheless, the functional remission rate in the CRANE cohort was as high as that in the early RA population receiving TNFi in clinical trials , ; this indicates that the targeted therapeutic strategy was effective in clinical practice for achieving a good outcome for physical function in patients with EORA.The use of TNFi is associated with overall risk of serious infection in Japanese RA patients , , particularly in the first year of treatment. Although the percentage of patients treated with biologics in the CRANE cohort was 31.0%, the incidence rate of serious infection in the CRANE cohort (12.6%) was numerically higher than those in Japanese RA populations from postmarketing surveillance (PMS) programmes for infliximab (8.6%), adalimumab (2.4%) and tocilizumab (3.6%) ,. Previous studies have demonstrated that age, chronic lung disease and the use of PSL are associated with serious infections ,. In fact, the mean age was much higher and chronic lung disease was more common in the CRANE cohort than in the PMS programmes, and 78.9% of the patients with serious infections in the CRANE cohort were receiving a relatively high dosage median 0.15 mg/kg/day (IQR 0.10–0.22 mg/day) of PSL.
In the elderly RA population, PSL was particularly associated with serious infection compared with biologics and nbDMARDs ,. Our data also suggest that the use of PSL hazard ratio (HR) 4.65 (95% CI 1.44, 15.0), P = 0.010 was associated with serious infections during 52 weeks, while the use of biologics was not HR 1.98 (95% CI 0.72, 5.53), P = 0.187 (see and, available at Rheumatology Online). However, we cannot conclude that biologics are relatively safe compared with PSL, since biologics were administered for only 3–6 months and the risk of biologics is underestimated.The clinical remission rate was lower in the CRANE cohort than in previous protocol-based tightly controlled studies and clinical practice. This difference from our results may be explained by variation in age, dose of MTX and treatment protocols including combination nbDMARDs across cohorts and high baseline disease activity, a relatively low rate of PSL use in initial treatment, delay in starting TNFi, inclusion of patients treated outside the targeted therapeutic strategy, less stringent treatment goals (LDA) and more co-morbidities found in the CRANE cohort. Recent studies have shown that combination nbDMARDs including PSL provide a high rate of clinical remission ,. On the other hand, only a few patients in the CRANE cohort were receiving combination nbDMARDs.
The dose of MTX was also an important factor in achieving remission. The mean dose of MTX in the CRANE cohort is much lower than the ACR/EULAR recommended dose , since the majority of our elderly patients have renal dysfunction or MTX-associated dose-dependent AEs. It should be noted that the mean dose by weight of MTX was comparable between the CRANE cohort and an elderly population in daily clinical practice in the USA.
Also, the targeted strategy with a relatively low dose of MTX resulted in functional remission in 63% of EORA patients and prevented the development of CRRP in 75% of EORA patients in the CRANE cohort.When interpreting the results of our study, some limitations must be considered. First, inherent limitations of a monocentric observational study must be considered. Since most elderly patients are referred from orthopaedists and other specialists in our hospital and medical service area, our patients may have higher disease activity and more co-morbidities than elderly patients with RA in the general population. This could mean the achievement of favourable outcomes is more challenging in our cohort. Nevertheless, 51.0% of the CRANE cohort achieved LDA and 24.8% achieved clinical remission. Second, we were unable to conclude that a therapeutic strategy targeting LDA was superior to other strategies in EORA because we did not have a control group.
Structural and physical outcomes were not statistically different between groups of non-adherence and adherence to the treat-to-target strategy. However, the non-adherent group was too small and baseline characteristics were different between the two groups. Thus the non-adherent group was not suitable as a control for evaluating superiority of the treat-to-target strategy. Third, we cannot determine that LDA is a better target than clinical remission in patients with EORA.
Our data suggest LDA is an acceptable target instead of clinical remission, because the rate (48.5%) of both structural and functional remission in patients who achieved LDA was comparable to that (50.0%) of patients who achieved clinical remission.In summary, we provide the first epidemiological evidence for a targeted therapeutic strategy for EORA in clinical practice and demonstrate that LDA, structural remission and functional remission in EORA patients are realistic goals. However, CRRP was not prevented in our study and EULAR no response at week 12 predicted progression of joint destruction in EORA.
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