Efficacy and safety of biological agents in the older rheumatoid arthritis patients compared to Young: A systematic review and meta-analysis

https://doi.org/10.1016/j.semarthrit.2018.07.009Get rights and content

Abstract

Objective

Biologic anti-rheumatic drugs are used with less frequency among older patients compared to young patients. This population is less represented in studies performed to evaluate the efficacy and safety of this drugs. We aimed to assess the efficacy and safety of biological agents between the older RA patients compared to young.

Methods

A comprehensive, systematic search was conducted in major indexing databases using key terms for RA and each biological agent. The review process was completed by 2 investigators. Both randomized controlled trials and observational studies of at least 6-month duration conducted in adult RA patients were included. Outcomes of interest were clinical efficacy and safety. Effect-estimates were pooled using random-effects modeling if 4 or more studies used the same scale and time-frame for measuring outcomes.

Results

24 studies (16 focusing on anti-TNF agents) representing 63,705 patients (24% were older) were included. Older RA patients had worse baseline RA disease activity, longer disease duration at the time of enrollment in the trial (14.4 ± 3.6 vs. 10.9 ± 3.6 years; p < 0.001) and higher steroid use (73.2 vs. 64.7%, p < 0.001) than younger. 5 out of 6 studies assessing anti-TNF agents showed worse efficacy outcomes in older patients. The pooled OR of infection and ADRs with anti-TNF agents in older compared to young RA patients was OR 1.59 (95% CI: 1.45–1.76) and 1.40 (95% CI: 1.23–1.61) respectively.

Conclusions

Older patients had worse safety and efficacy with biological agents but also had worse baseline disease activity. There was significant heterogeneity in reporting outcomes and very limited studies in biological agents other than anti-TNF drugs.

Section snippets

Background

Rheumatoid arthritis (RA) is a chronic systemic inflammatory arthritis an average age of onset at 55 years [1]. About one-third of patients acquire the disease after the age of 60–65, conventionally classified as “late” or “elderly” onset RA. Given the chronic nature of the disease, average RA patients can expect to have the disease well into their senior years [2], [3]. In fact, the prevalence of RA in older population is twice of what is noted across all ages (app. 2% v. 1) [4], [5]. In

Methods

Search strategy: We formulated the research question using the PECOS format. The population was adult rheumatoid arthritis patients using biologics including tofacitinib, the exposure and comparison groups were old and young RA patients, outcomes were clinical efficacy and safety, and study designs included were randomized controlled trials (RCT) and observational trials (both cohort and case-control studies).

A systematic literature search was performed to identify studies indexed until April

Results

A total of 5353 articles were retrieved with the systematic search and after eliminating exact duplicates. After title/abstract screening and including 17 articles from references of prior review articles, 185 articles were included for full-text review; 32 studies fulfilled inclusion criteria (Fig.1). Eight articles focused on efficacy, 15 on safety and 9 on both. Among these, 22 articles (69%) focused on anti-TNF agents, 4 on tocilizumab, 2 on abatacept, 2 on tofacitinib, 1 on rituximab and 1

Baseline disease activity

Nine out of the 24 articles (37.5%) provided baseline disease activity in form of DAS-28, ESR, CRP or erosive disease by age group [44], [46], [51], [52], [53], [54], [55], [56], [57]. Baseline DAS28 was reported in each of these articles and was comparable between older and young RA groups (5.33 ± 0.48 vs. 5.08 ± 0.48, p = 0.35, n = 7 ) [46], [51], [52], [54], [55], [56], [57]. Baseline CRP was recorded only in 4 articles [46], [51], [52], [56], ESR in 5 [46], [51], [52], [54], [56] and

Efficacy outcomes (Tables 2a and 2b)

Most of the efficacy studies focused on anti-TNF agents (9/13, 69%), 2 each on abatacept and abatacept and 1 each on tocilizumab and rituximab. Across all studies, there was significant heterogeneity in reporting outcomes including the use of odds of remission by DAS28, odds of remission by EULAR response criteria, change in DAS28, ACR response criteria, EULAR response, change in HAQ-DI, change in CDAI and change in SDAI. Further, these were reported at different times of follow-up ranging from

Safety outcomes (Tables 2a and 2b)

Nineteen articles focussed on the safety of biologics; 12 (63%) of these focused on anti-TNF drugs, 3 on tocilizumab, 2 of tofacitinib, 1 each on abatacept and rituximab. Infection and serious infections were the focus of 16 articles (70%), 7 (29%) focused on ADR, 3 focused on malignancy and 2 on zoster.

8 studies of the 12 studies focussing on anti-TNF agents evaluated infections as an outcome; of these 2 (Bathon et al and Flieschmann et al) used the same underlying cohort. The study by Bathon

Discussion

This systematic review and meta-analysis identified 32 articles which compared the efficacy and safety outcomes in older and young RA patients. We noted significant heterogeneity in defining older RA patients and hence we focussed our primary analyses among studies which use 60–65years of age to define older RA population (24 studies). The majority of the included studies showed reduced efficacy and safety of biologics in older RA patients compared to young. Meta-analyses of studies focusing on

Conclusions

The current systematic review and meta-analyses shows a reduced benefit-to-risk ratio of biologic agents in the older RA population. However, this observed effect may be reflective of biases inherent to observational studies and reflective of the current clinical practices. Further, the non-intensification of RA therapy to include biological agents in older patients would lead to increased use of non-steroidal anti-inflammatory agents, glucocorticoids in combination with synthetic DMARDs which

Acknowledgment

We would like to acknowledge Barbara Davis for her assistance with developing a comprehensive search strategy.

Conflicts of interest

None.

References (77)

  • YM Pers et al.

    Efficacy and safety of tocilizumab in elderly patients with rheumatoid arthritis

    Joint Bone Spine Revue du Rhumatisme

    (2015)
  • B Nguyen-Khoa et al.

    Risk of significant infection in rheumatoid arthritis patients switching anti-tumor necrosis factor-î± drugs

    Sem Arthritis Rheum

    (2012)
  • ChiangYC et al.

    Infection risk in patients with rheumatoid arthritis treated with etanercept or adalimumab

    Comput Methods Programs Biomed

    (2014)
  • M Soubrier et al.

    Rheumatoid arthritis in the elderly in the era of tight control

    Drugs Aging

    (2013)
  • I Olivieri et al.

    Management issues with elderly-onset rheumatoid arthritis: an update

    Drugs Aging

    (2005)
  • EK Rasch et al.

    Prevalence of rheumatoid arthritis in persons 60years of age and older in the United States: effect of different methods of case classification

    Arthritis Rheum

    (2003)
  • Department of economic and social affairs, population division

    (2013)
  • GR Boss et al.

    Age-related physiological changes and their clinical significance

    West J Med

    (1981)
  • DP Zoller

    The physiology of aging

    Am Fam Phys

    (1987)
  • Promoting Cardiovascular Health in the Developing World: A Critical Challenge to Achieve Global Health. Editors...
  • JA Singh et al.

    2015 American college of rheumatology guideline for the treatment of rheumatoid arthritis

    Arthritis Rheumatol

    (2016)
  • Y Yazici et al.

    Utilization of biologic agents in rheumatoid arthritis in the United States: analysis of prescribing patterns in 16,752 newly diagnosed patients and patients new to biologic therapy

    Bull NYU Hosp Jt Dis

    (2008)
  • M Dougados et al.

    Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA)

    Ann Rheum Dis

    (2014)
  • FC Breedveld et al.

    The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment

    Arthritis Rheum

    (2006)
  • SB Cohen et al.

    Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks

    Arthritis Rheum

    (2006)
  • R Fleischmann et al.

    Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study

    Ann Rheum Dis

    (2009)
  • MC Genovese et al.

    Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition

    N Engl J Med

    (2005)
  • LW Moreland et al.

    Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial

    Ann Intern Med

    (1999)
  • M Schiff et al.

    Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate

    Ann Rheum Dis

    (2008)
  • ME Weinblatt et al.

    Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial

    Arthritis Rheum

    (2003)
  • LR Harrold et al.

    Time trends in medication use and expenditures in older patients with rheumatoid arthritis

    Am J Med

    (2012)
  • NgB et al.

    A retrospective cohort study: 10-year trend of disease-modifying antirheumatic drugs and biological agents use in patients with rheumatoid arthritis at Veteran Affairs Medical Centers

    BMJ Open

    (2013)
  • BJ Radovits et al.

    Missed opportunities in the treatment of elderly patients with rheumatoid arthritis

    Rheumatology (Oxford)

    (2009)
  • Z Tutuncu et al.

    Do patients with older-onset rheumatoid arthritis receive less aggressive treatment?

    Ann Rheum Dis.

    (2006)
  • LF Hutchins et al.

    Underrepresentation of patients 65years of age or older in cancer-treatment trials

    N Engl J Med

    (1999)
  • A Kumar et al.

    National Cancer Institute. Treatment tolerance and efficacy in geriatric oncology: a systematic review of phase III randomized trials conducted by five National Cancer Institute-sponsored cooperative groups

    J Clin Oncol

    (2007)
  • M van Onna et al.

    The challenging interplay between rheumatoid arthritis, ageing and comorbidities

    BMC Musculoskelet Disord

    (2016)
  • T Sugihara et al.

    Targeting low disease activity in elderly-onset rheumatoid arthritis: current and future roles of biological disease-modifying antirheumatic drugs

    Drugs Aging

    (2016)
  • Cited by (19)

    • Nanoparticle-siRNA: A potential strategy for rheumatoid arthritis therapy?

      2020, Journal of Controlled Release
      Citation Excerpt :

      The mechanism of action of immunosuppressants is to resist the body's excessive immune response, and at the same time it will inhibit the body's normal defense capabilities, so there will be a great risk of causing body infections and even cancer. Although biological agents can still play a good therapeutic effect in patients with advanced RA or RA patients who are not effective in the treatment of DMARDs, the long-term application of biological agents brings high costs, risks of infection and other risks that still limit the clinical application of biological agents [66,75–77]. The current treatment methods for side effects in RA drug therapy often include drug replacement therapy, or change the dose, or symptomatic treatment.

    • Applicability of trials in rheumatoid arthritis and osteoarthritis: A systematic review and meta-analysis of trial populations showing adequate proportion of women, but underrepresentation of elderly people

      2019, Seminars in Arthritis and Rheumatism
      Citation Excerpt :

      As one example, thrombolytic and interventional therapy is associated with higher mortality in older patients with myocardial infarction, while the elderly had similar response and survival rates in trials on lung and breast cancer [50–53]. Recent research suggests lower response rates to biologicals in elderly RA patients and a diminished benefit-to-risk ratio [54–56]. Of all 265 RCT included in our study, only five analyzed age as a determinant for outcome.

    • Antirheumatic drugs in older adults and polypharmacy issues

      2022, Zeitschrift fur Gerontologie und Geriatrie
    View all citing articles on Scopus

    Funding: Internally funded; no external funding obtained.

    View full text