A total of 3286 publications were found from the literature search. After excluding duplicates, irrelevant and ineligible studies, 86 studies remained. 15 studies using the same cohorts (or subsets thereof) were excluded. The study by Rojas-Vargas et al was excluded as it only included patients with ≤2 years of symptoms. The selection flowchart is shown in Supplementary Figure S1. The 66 included studies are summarised in Supplementary Table S1. 55 studies reported delays among axSpA patients, 8 PsA and 5 SpA. Feld et al [10] and Sørensen et al [11] reported delay in both axSpA and PsA. Bias scores were mostly 2 to 4 out of 6 stars (Supplementary Table S2 and Figure S2) indicating moderate bias.
Diagnostic delay in axSpA
Sample size for axSpA studies ranged from 5 to 2,887 patients. 38 studies were of AS (including 25 using modified New York criteria) and 18 of axSpA (including 11 using the ASAS criteria). Delay ranged from 2.8 years in a small Albanian study (of 54 cases over 6 years), to 11.1 years in a single UK centre [12,13]. The mean delay to diagnosis was 6.8 years overall (95% confidence interval 6.2 to 7.3, I2=99%).
Results of stratified meta-analysis are shown in Table 2. 38 axSpA studies were from countries in the European region, 7 West Pacific, 7 Eastern Mediterranean, 4 Americas and 3 South East Asia. Across these WHO regions, the mean delay and heterogeneity were not significantly different. When these studies were stratified according to World Bank economic class, the High-income group had longer mean delays than the upper- and lower-middle income countries. When mean delays were pooled according to country (with ≥3 studies), the average diagnostic delay was significantly shorter in Turkey than in the UK. Mean delay duration did not differ according to year of publication or disease definition. Studies with older mean age of symptom onset showed trends for shorter delay durations.
When the above study characteristics were entered into a multivariable meta-regression model, only economic status was significantly associated with mean delay duration (Supplementary Table S2). Countries in the upper- and lower-middle income category had shorter mean delay by 2.8 and 4.1 years, respectively.
Sensitivity analyses (for mean delay and meta-regression) excluding studies with imputed mean and/or standard deviation of delay produced similar results (data not shown).
Table 1. Meta-analysis of delay duration stratified by study characteristics.
|
|
n
|
mean delay
|
95% CI
|
I2
|
World Health Organisation regions
|
European
|
34
|
7.02
|
6.31, 7.73
|
98.2%
|
West Pacific
|
7
|
6.43
|
4.49, 8.37
|
96.8%
|
Eastern Mediterranean
|
7
|
6.62
|
5.37, 7.88
|
90.4%
|
Americas
|
4
|
5.76
|
2.63, 8.89
|
98.7%
|
South East Asia
|
3
|
6.38
|
-1.40, 14.15
|
96.7%
|
World Bank economic class
|
High
|
34
|
7.61
|
7.03, 8.18
|
97.4%
|
Upper middle
|
16
|
5.38
|
4.46, 6.30
|
96.8%
|
Lower middle
|
5
|
5.59
|
3.21, 7.96
|
95.7%
|
Countries with ≥3 studies
|
UK
|
8
|
8.69
|
7.14, 10.23
|
94.9%
|
Turkey
|
8
|
5.54
|
4.39, 6.68
|
90.4%
|
Italy
|
3
|
7.68
|
2.67, 12.69
|
99.6%
|
Iran
|
3
|
7.35
|
4.83, 9.87
|
79.5%
|
China
|
3
|
4.61
|
1.47, 7.75
|
85.6%
|
Recruiting methods
|
Single centre
|
32
|
6.60
|
5.84, 7.36
|
98.5%
|
>1 centre
|
23
|
7.02
|
6.23, 7.83
|
98.8%
|
Year of publication
|
<2010
|
8
|
7.08
|
5.87, 8.30
|
95.4%
|
2010-15
|
25
|
6.82
|
5.93, 7.70
|
97.3%
|
>2015
|
22
|
6.61
|
5.70, 7.53
|
99.3%
|
Disease definition
|
Ankylosing spondylitis
|
38
|
6.54
|
5.90, 7.19
|
97.9%
|
Axial spondyloarthritis
|
17
|
7.26
|
6.22, 8.30
|
98.5%
|
Age at symptom onset (tertiles)
|
22.7 - 24.2 years
|
10
|
7.37
|
6.11, 8.64
|
98.0%
|
24.4 - 27.1 years
|
11
|
7.70
|
6.59, 8.81
|
94.5%
|
27.3 - 35 years
|
11
|
6.33
|
4.50, 8.16
|
99.1%
|
Proportion of males (tertiles)
|
39-68%
|
17
|
7.05
|
6.09, 8.01
|
98.7%
|
68-80%
|
17
|
7.52
|
6.55, 8.48
|
95.0%
|
80-100%
|
18
|
5.70
|
4.91, 6.48
|
94.8%
|
Factors associated with delay to diagnosis
Most results were from unadjusted comparisons (table 2). Delay was reportedly longer in males in studies by Bandinelli (10 v 6.3 years, p=0.002) and Sykes (9.4 v 8.3, p=0.097) [4,14], but longer in females in studies by Fallahi (8.7 v 7.7, p=0.68), Dincer (14 v 5.3, p=0.06), Hajialilo (8.0 v 5.9, p=0.14), Jones (8.5 v 5.6) and Redeker (by 1.9yrs, p<0.05) [15–19], albeit mostly not statistically significant. Similarly, 2 studies reported longer delay in those with peripheral arthritis [15,17], while 5 reported longer delays in those without [4,6,14,20,21]. There was also inconsistency in whether studies found HLA-B27 status to be associated with diagnostic delay: 4 studies reported significantly longer delays in HLA-B27 negative patients [15,16,19,22], while 5 other studies did not [14,20,21,23,24].
There was better consensus among the studies that longer delay was associated with: the absence of EAMs [4,17,23], lower education [15,16,20,25], and younger age of onset [19,20,24,25].
Table 2 Factors associated with longer delay to diagnosis in axial spondyloarthritis (results reported as mean duration in years).
|
Aggarwal 2009 [23]
|
Absence EAMs v presence (8.7 vs 5.9, p=0.03)
Onset <16 v >16 yrs (9.1 v 6.1, p=0.03)
|
Bandinelli 2016 [14]
|
Male v females (10 vs 6.3, p=0.002)
Manual v non-manual workers (11 vs 8.3, p=0.047)
Axial presentations compared to arthritis or enthesitis (9.0 vs 8.5 vs 4.3, p=0.002)
Lower education (<high school v high school v university: 10 v 8.6 v 7.3, p=0.076)
|
Dincer 2008 [16]
|
HLA-B27 negative v positive (9.2 vs 5.3, p=0.037)
Family history v none (10 vs 4.6 p=0.003)
Onset ≤16 v >16 yrs (8.9 v 5.5, p=0.027)
Lower education (<9yrs v 9-11 v 12-13 v 14-15: 12 v 6.3 v 5.0 v 4.6, p=0.018)
Females v males (14 v 5.3, p=0.061)
|
Fallahi 2016 [15]
|
Enthesitis v no enthesitis (8.8 vs 6.0, p=0.007)
HLA-B27 negative v positive (10 vs 7.1, p=0.013)
Lower education (correlation r=0.24 p=0.002)
Presence of peripheral arthritis v absence (8.9 v 6.8, p=0.086)
|
Feldtkeller 2003 [22]
|
HLA-B27 negative v positive (11 v 8.5, p<0.01)
|
Gerdan 2012 [25]
|
With v without prior diagnosis of lumbar disc herniation (9.1 vs 6.2, p=0.002)
First contact being rheumatology v non-rheumatology (8.1 vs 2.9, p<0.001)
Younger age at onset (b=-0.18, p=0.003)
Lower education (b=-0.252, p=0.018)
|
Hajialilo 2014 [17]
|
Presence of peripheral arthritis v absence (11 vs 5.1 p<0.001)
Absence of uveitis v presence (6.4 v 2.4 p=0.02)
Presence of heal pain v absence (13 v 5.9 p=0.004)
Females v males (8.0 v 5.9, p=0.14)
|
Jones 2014 [18]
|
Females v males (8.5 vs 5.6)
|
Masson Behar 2017 [20]
|
Univariable regression showed longer delay with
Older age at diagnosis (b=0.15 p<0.001)
Lower education (b=-1.7 p=0.03)
Later calendar year of diagnosis (0.1 p=0.005)
Multivariable regression showed longer delay with
Older age at diagnosis (b=0.1, p<0.001)
Entheseal pain v none (b=1.5 p=0.015)
Absence of peripheral arthritis/dactylitis v presence (b=-1.7, p=0.005)
|
Nakashima 2016 [21]
|
Absence articular involvement vs presence (8.9 v 5.2, p=0.03)
Disease onset pre-2000 v post (7.5 v 3.5 p=0.02)
|
Reed 2008 [26]
|
Delay longer with later calendar year and younger age at onset (p<0.05)
|
Seo 2015 [6]
|
Long-delay (v short delay <=8 years) category associated with:
Absence of peripheral symptoms (OR 2.2, p=0.06)
Prior diagnosis of mechanical back pain (OR 2.8, p=0.02)
In univariate analysis, mechanical back pain remained significant in multivariable model
|
Sykes 2015 [4]
|
Absence of peripheral arthritis vs presence (9.4 v 7.6, p=0.045)
Absence of IBD v presence (9.2 v 6.5, p=0.012)
Presence of uveitis vs absence (10 v 8.4, p=0.033)
Females v males (9.4 v 8.3, p=0.097)
|
Redeker 2018 (abstract) [19]
|
Multivariable regression showed longer delay in
Female v males (b=1.9, 95%CI 1.1 2.7)
Younger age of symptom onset, per 10yrs (-1.9, 95%CI -2.3, -1.5)
HLA-B27 negative v positive (-3.6, 95%CI -5.1, -2.1)
Psoriasis v no psoriasis (1.4, 95%CI 0.1, 2.7)
|
Resende 2018 (abstract) [24]
|
Presence of EAMs v absence (8.7 v 5.0, p<0.001)
Younger age onset (r=-0.28, p<0.001)
|
EAM, extra-articular manifestations (anterior uveitis, psoriasis, inflammatory bowel disease)
|
PsA and SpA
Sample size for PsA studies ranged from 69 to 1970 patients. Diagnostic delay ranged from 1.0 years in the Dutch South-West Psoriatic Arthritis to 4.6 in a Swedish population-based cohort [27,28]. The mean delay to PsA diagnosis was 2.6 years (95%CI 1.6 to 3.6, I2=99%) (Figure 2). SpA studies ranged from 16 to 275 participants in size and 1.6 to 7.6 years in diagnostic delay. The mean delay to SpA diagnosis was 4.2 years (95%CI 2.1 to 8.1, I2=96%) (Figure 2).