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Background: As the global population ages, more older adults are living with autoimmune rheumatic diseases (AIRDs). However, they remain underrepresented in randomized controlled trials (RCTs). This limits applicability of trial evidence to routine care, particularly given age-related differences in comorbidity burden, treatment tolerance, drug metabolism, and safety considerations. A comprehensive, cross-disease assessment of age-related inclusion practices in AIRD trials has not been performed.
Objectives: To evaluate the inclusion of older adults in pharmacologic RCTs across AIRDs and compare the age distribution of trial participants with contemporary real-world populations.
Methods: We conducted a systematic review and meta-analysis (PROSPERO CRD42023457996) of phase II–IV pharmacologic RCTs published 2010–2023 (2017–2023 for RA). Searches covered major bibliographic databases and trial registries. Eligible RCTs enrolled adults (≥18 years for most AIRDs, ≥15 years for AAV and SLE) with AAV, GCA/PMR, IIM, RA, SLE, SpA, or SSc and reported age eligibility criteria and baseline age.
Two reviewers screened and extracted data. Mean age and proportion of older adults were calculated using methods developed by Palmowski 1 based on truncated normal distributions. Pooled estimates were generated using random-effects models. Rheumatology Informatics System for Effectiveness (RISE) registry 2023 data provided comparator mean age and proportion ≥65 years.
Results: We identified 514 RCTs including 152,538 participants across seven AIRDs (Table 1). RA, SpA, and SLE comprised most trials and participants. Only 46.9% of RCTs reported any age-stratified data for older adults.
Mean age of participants varied substantially by AIRD (Table 2). Across all conditions, RCTs enrolled younger populations than those seen in practice. For example, RA trials had a pooled mean age of 53.6 years compared with 63.4 years in the RISE registry. The proportion of older adults (≥65 years) was also markedly lower; RA trials enrolled 19.4% older adults versus 49.9% in RISE. SLE and SpA showed even larger proportional discrepancies.
Substantial heterogeneity was observed for both pooled mean age and the proportion of older adults (I 2 ≥75%), indicating wide variation in age inclusion across trials within each AIRD. Upper age exclusion criteria were common in several conditions, including SLE (56.0%), IIM (55.6%), and RA (40.1%), with median upper limits typically around 70–75 years, while GCA/PMR rarely imposed such criteria.
Conclusions: Older adults are underrepresented in RCTs across AIRDs. These findings underscore the importance of age-related inclusion strategies, standardized reporting of age and age-related exclusions, and the systematic consideration of older adults during trial planning. Improving representation of older adults is critical for ensuring future evidence is applicable, interpretable, and actionable for clinicians caring for older adults living with AIRDs.
Characteristics of included RCTs across AIRD
| AAV | GCA/PMR | IIM | RA | SLE | SpA | SSc | |
|---|---|---|---|---|---|---|---|
| Number of trials included | 27 | 10 | 18 | 172 | 100 | 141 | 46 |
| Number of participants, n (median; range) | 3,485
| 718
| 1,307
| 72,614
| 26,912
| 43,751
| 3,751
|
| Female, sex | 1,608 (46.1) | 506 (70.5) | 782 (59.8) | 57,218 (78.8) | 24,838 (92.3) | 17,837 (40.8) | 2,823 (75.3) |
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| Presented as n (%), unless specified otherwise.
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Mean ages and inclusion of older adults in RCTs across AIRD and contemporary population data
| Variable | AAV | GCA/PMR | IIM | RA | SLE | SpA | SSc |
|---|---|---|---|---|---|---|---|
| RCTs | |||||||
| Age, mean (95% CI) | 59.3
| 69.9
| 54.6
| 53.6
| 38.0
| 43.4
| 49.4
|
| With upper age exclusion criteria, n (%) | 12 (44.4) | 1 (10) | 10 (55.6) | 69 (40.1) | 56 (56.0) | 41 (29.1) | 16 (34.8) |
| Median age for upper limit exclusion criteria, IQR | 77 (75-80) | 85 (85-85) | 75 (75-80) | 75 (75-80) | 70 (65-75) | 70 (65-75) | 70 (65-75) |
| Proportion of participants aged ≥65 years, % (95% CI) | 38.5
| 71.6
| 24.5
| 19.4
| 1.27
| 6.1
| 10.2
|
| RISE Registry | |||||||
| Number of participants | 2,946 | 18,910 | 4,718 | 204,446 | 36,201 | 74,739 | 5,924 |
| Age, mean (SD) | 62.4 (14.9) | 74.6 (9.0) | 61.0 (14.7) | 63.4 (13.6) | 54.3 (15.3) | 56.6 (14.1) | 63.2 (13.1) |
| Proportion of participants aged ≥65 years, (%) | 49.7 | 85.6 | 44.0 | 49.9 | 26.7 | 30.5 | 49.5 |
| RCT=randomized clinical trial, AIRD=autoimmune rheumatic disease, AAV=ANCA-associated vasculitis, GCA=Giant cell arteritis, PMR=polymyalgia rheumatica, IIM=Idiopathic inflammatory myopathies, RA=rheumatoid arthritis, SLE=Systemic lupus erythematosus, SpA=Spondyloarthritis, SSc=Systemic sclerosis, SD=standard deviation, IQR=interquartile range | |||||||
REFERENCES: NIL.
Acknowledgments: NIL.
Disclosure of Interests: None declared.