This systematic literature review analyzed the available literature on the clinical, economic, and humanistic burden of delayed diagnosis among patients with axial spondyloarthritis (axSpA). |
Overall, patients with delayed diagnosis of axSpA had worse clinical outcomes, including higher disease activity, worse physical function, and more structural damage, compared with patients who had an earlier diagnosis |
Moreover, patients with a delayed diagnosis had higher healthcare costs and greater likelihood of work disability compared with those with an earlier diagnosis. |
Delayed diagnosis was largely associated with worse quality of life, including greater likelihood for depression and negative psychological impact. |
Our study emphasizes the value of early recognition of axSpA to enhance clinical outcomes and improve patient and societal burden. |
Plain Language Summary
Introduction
Methods
Data Sources
Eligibility Criteria and Article Selection
Databases | Electronic databases: MEDLINE, MEDLINE In-Process, and Embase Conference databases: ACR/ARHP Annual Meeting and EULAR Annual European Congress of Rheumatology archives |
Time frame | Full-text articles: database start to July 12, 2018 Conference abstracts: January 1, 2013, to July 12, 2018 |
Inclusion criteria | Population: adult patients with axSpA Outcomes Clinical: comorbidities, mortality, and disability and functional status (e.g., BASDAI, BASFI, BASMI) Economic: direct/indirect costs, resource use data, type of cost data and value, and type of resource use and value Humanistic: HRQOL and utility values and qualitative measures Study design: original research studies, including observational studies; claims database studies; surveys; and any study reporting cost, resource use, and HRQOL data |
Exclusion criteria | Animal/in vitro studies and studies with children or patients with peripheral spondyloarthritis Non-English-language articles Interventional studies, including RCTs, nRCTs, or single-arm trials HTAs, reviews, editorials, case reports, and case series |
Critical appraisal tools | Downs and Black Quality Index for assessing risk of bias [48] |
Data extraction | Total number of patients analyzed, number of patients with outcome, mean, SD, SE, median, range, 95% CI, and P values, as applicable |
Data Extraction and Quality Assessment
Results
Study Selection, Characteristics, and Quality Assessment
Study | Study design | Country | Patient population [N] | Male, % | Age, mean (SD), yearsa | Disease duration, mean (SD), years | Diagnostic delay, mean (SD), years | Outcome |
---|---|---|---|---|---|---|---|---|
Nie A, et al. 2018 | Single center, cross-sectional | China | AS [281] | 68.0 | 31.7 (9.8) | 7.9 (7.4) | 4.3 (5.3) | Clinical |
Zhao J, et al. 2015 | Cross-sectional | China | AS [256] | 88.3 | Onset: 22.9 (5.5) Diagnosis: 34.0 (8.3) | 10.1 (7.3) | 3.9 (2.0) | Clinical |
Seo MR, et al. 2015 | Cross-sectional | Korea | AxSpA [94] | 78.7 | Median (IQR) Enrollment: 40 (30–49) Onset: 23 (17–30) Diagnosis: 35 (24–43) | Median (IQR) 14 (8–21) | Median (IQR) 8 (3–15) | Clinical, economic |
Aggarwal R, et al. 2009 | Cross-sectional | India | AS [70] | 84.3 | Onset: 23.6 (8.8) Diagnosis: 32.5 ± 9.7 | NR | 6.9 (5.2) | Clinical |
Gunasekera W, et al. 2014 | Retrospective observational | UK | AS [106] | 79.0 | Onset: 24.5 (9.8) Diagnosis: 35.5 (14.0) | NR | 10.5 (11.9) | Clinical, economic |
Martindale J, Goodacre L. 2014 | Longitudinal cohort | UK | AS/ AxSpA [10] | 70.0 | 40.2 (7.7) | NR | NR | Humanistic |
Fitzgerald G, et al. 2017 | Retrospective observational | Ireland | AxSpA [564] | 78.2 | 47.1 (12.4) | 20.8 (12.2) | 8.6 (8.0) | Humanistic |
Sullivan C, et al. 2014 | Retrospective observational | Ireland | AS [92] | 80.4 | 46.7 (range, 23–80) | NR | 6.0 (4.8) | Clinical, economic |
Sullivan C, FitzGerald O. 2011 | Cross-sectional | Ireland | AS [59] | 59.0 | Onset: 25 Diagnosis: 32 | NR | 7.3 (range, 0–23) | Economic |
Mennini FS, et al. 2018 | Retrospective observational | Italy | AxSpA [1084] | 35.1 | 43.3 (NR) | NR | NR | Economic |
Abdelrahman FI, Mortada M. 2018 | Cross-sectional | Egypt | AxSpA [126] | Before 2010: 87.5; After 2010: 80.0 | Diagnosis: Before 2010: 34.9 (6.4) After 2010: 25.8 (4.5) | NR | Before 2010: 11.3 (3.9) After 2010: 4.6 (2.8) | Clinical, economic |
Abdul-Sattar A, Abou El Magd S. 2017 | Cross-sectional | Egypt | AS [190] | 94.4 | 37.8 (9.7) | 12.1 (8.9) | 6.3 (2.6) | Economic |
Ibn YY, et al. 2012 | Cross-sectional | Morocco | AS [100] | 67.0 | Enrollment: 38.0 (13.0) Diagnosis: 32.7 (11.6) | 9.2 (6.8) | 4.1 (4.0) | Clinical |
Fallahi S, Jamshidi AR. 2016 | Cross-sectional | Iran | AS [163] | 79.1 | Enrollment: 37.7 (9.9) Onset: 23.4 (7.1) Diagnosis: 31.3 (9.7) | Median (IQR) 12 (6–20) | 7.9 (7.2) | Clinical, humanistic |
Hajialilo M, et al. 2014 | Cross-sectional | Iran | AS [60] | 88.3 | Diagnosis: 36.4 (4.5) | NR | 6.2 (3.5) | Clinical |
Alayli G, et al. 2015 | Retrospective observational | Turkey | AS [85] | 74.1 | Enrollment: 36.7 (11.0) Onset: 24.8 (8.8) Diagnosis: 29.9 (9.9) | 11.0 (5.6) | 5.1 (7.2) | Clinical |
Cakar E, et al. 2009 | Prospective observational | Turkey | AS [121] | 100 | 31.6 (10.5) | 9.1 (6.9) | No change with work: 3.7 (3.6) Change to lighter workload: 7.3 (4.8) Permanently work-disabled: 7.8 (6.9) | Clinical, economic, humanistic |
Dincer U, et al. 2008 | Cross-sectional | Turkey | AS [111] | 92.7 | Enrollment: 33.6 (12.0) Onset: 23.2 (9.6) Diagnosis: 27.9 (11.6) | 10.4 (8.1) | 6.1 (5.1) | Clinical |
Slobodin G, et al. 2011 | Retrospective observational | Israel | AxSpA [148] | 52.3 | Diagnosis: Men: 35.6 (11.7) Women: 38.5 (12.3) | NR | Men: 5.9 (60.4) Women 5.7 (6.0) | Clinical |
Cayetti LA, et al. 2013 | Prospective observational | Argentina | AS [147] | 75.5 | Median (IQR) 46 (18–35) | NR | Median (IQR) 5 (2–13) | Clinical, humanistic |
Grigg SE, et al. 2011 | Cross-sectional | Australia | AS [127] | NR | Onset: 23.9 (9.3) | NR | 10.0 (8.9) | Humanistic, economic |
Clinical Burden of Delayed Diagnosis
Study | Patient population [N] | Definition of delay, years | Clinical outcome measures | Patient outcomes |
---|---|---|---|---|
Nie A, et al. 2018 | AS [281] | Continuous | PSQI | Longer delay significantly correlated with higher PSQI scores (β = 0.174; P = 0.001) |
Zhao J, et al. 2015 | AS [256] | ≤ 5 vs. > 5 | BASRI-hip | Delay of > 5 years positively associated with more severe hip disease (OR, 2.35 [95% CI, 1.36–4.08]; P = 0.002) |
Seo MR, et al. 2015 | AxSpA [94] | ≤ 8 (late diagnosis) vs. > 8 (early diagnosis) | CRP ESR BASDAI BASFI Modified Schober test Radiographic sacroiliitis III or IV Spine bony change mSASSS ACR functional class III or IV | Significant differences between late vs. early diagnosis at time of diagnosis: Modified Schober test: median (IQR), 2.7 (1.6–4.4) vs. 6.0 (2.5–6.0) cm; P = 0.03 mSASSS: median (IQR), 21.0 (3.0–42.0) vs. 0 (0–4.5); P < 0.01 Proportion with spine bony changes: 77.4 vs. 44.8%; P < 0.01 Significant differences between late vs. early diagnosis at time of study: BASDAI: median (IQR), 3.4 (2.0–4.9) vs. 2.0 (1.0–4.2); P = 0.01 BASFI: median (IQR), 2.5 (0.3–3.8) vs. 0.7 (0.1–1.4); P < 0.01 Modified Schober test: median (IQR), 2.8 (1.2–4.5) vs. 4.5 (3.3–5.3) cm; P < 0.01 mSASSS: median (IQR), 26.0 (4.8–46.3) vs. 1.0 (0–12.5); P < 0.01 Proportion with spine bony changes: 85.3 vs. 53.6%; P < 0.01 |
Aggarwal R, et al. 2009 | AS [70] | ≤ 5.9 vs. > 5.9 | BASDAI BASFI BASMI | Patients with delay of > 5.9 years had significantly worse mean (SD) scores than those with delay of ≤ 5.9 years BASDAI: 3.7 (1.8) vs. 2.7 (1.7); P = 0.035 BASFI: 3.8 (2.4) vs. 2.5 (2.1); P = 0.033 BASMI: 3.3 (2.7) vs. 1.5 (2.2); P = 0.012 |
Gunasekera W, et al. 2014 | AS [106] | Continuous | BASDAI BASFI BASMI | BASMI score increased by 0.06 per year of diagnosis delay (P = 0.0002) No significant impact of diagnosis delay on BASDAI or BASFI |
Sullivan C, et al. 2014 | AS [92] | < 4 vs. 5–9 vs. > 10 vs. unknown | BASDAI BASFI BASMI | No significant differences in BASDAI, BASFI, or BASMI scores |
Abdelrahman FI, Mortada M. 2018 | AxSpA [126] | Mean (SD) Before 2010: 11.3 (3.9) After 2010: 4.6 (2.8) | BASDAI BASFI BASMI | Patients with longer delay had worse mean (SD) scores than those with shorter delay (all P < 0.001): BASDAI: 9.1 (1.4) vs. 4.3 (2.2) BASFI: 9.1 (1.4) vs. 3.9 (2.2) BASMI: 8.9 (1.2) vs. 2.2 (2.0) |
Ibn YY, et al. 2012 | AS [100] | < 5 vs. ≥ 5 | CRP ESR BASDAI BASFI BASRI Occiput-to-wall distance Chest expansion Schober test | Patients with delay of ≥ 5 years had significantly greater BASFI (61.4 vs. 51.1) and BASRI (8.4 vs. 5.7) scores and significantly lower chest expansion (2.2 vs. 3.5 cm) and Schober test result (1.7 vs. 2.8 cm) than those with delay of < 5 years (all P < 0.05) Longer diagnostic delay was significantly correlated with: Occiput-to-wall distance: r = 0.317 (P = 0.001) Chest expansion: r = 0.374 (P > 0.001) Schober test: r = −0.368 (P < 0.001) BASFI: r = 0.289 (P = 0.004) BASRI: r = 0.349 (P < 0.001) No impact of diagnostic delay on BASDAI score, ESR, or CRP level |
Fallahi S, Jamshidi AR. 2016 | AS [163] | Continuous | BASDAI BASFI BASMI Chest expansion Finger-to-floor distance Intermalleolar distance Modified Schober test Cervical rotation Tragus-to-wall distance Sacroiliitis grading | Longer diagnostic delay significantly correlated with worse outcomes: BASDAI: r = 0.18 (P = 0.026) BASFI: r = 0.23 (P = 0.003) BASMI: r = 0.41 (P < 0.001) Chest expansion: r = −0.38 (P < 0.001) Finger-to-floor distance: r = 0.27 (P < 0.001) Intermalleolar distance: r = −0.18 (P = 0.022) Modified Schober test: r = −0.33 (P < 0.001) Cervical rotation: r = −0.29 (P < 0.001) Tragus-to-wall distance: r = 0.30 (P < 0.01) Sacroiliitis grading: r = 0.16 (P = 0.042) |
Hajialilo M, et al. 2014 | AS [60] | < 3 vs. > 3 | BASDAI BASFI | Patients with delay of > 3 years had significantly worse BASFI scores (mean [SD], 4.1 [0.7] vs. 3.3 [1.0]; P = 0.001) but comparable BASDAI scores vs. patients with delay of < 3 years |
Alayli G, et al. 2015 | AS [85] | Continuous | BASDAI BASFI BASMI mSASSS | Delayed diagnosis positively correlated with BASFI and BASMI scores and mSASSS but not with BASDAI scores |
Cakar E, et al. 2009 | AS [121] | Mean (SD) No change in work: 3.7 (3.6) Work-disabled, change in job: 7.3 (4.8) Permanently work disabled: 7.8 (6.9) | CRP ESR BASFI BASDAI BASMI Modified lumbar Schober test Lateral lumbar flexion Chest expansion Chin-to-sternum distance Tragus-to-wall distance Intermalleolar distance | Patients with longer delay had higher CRP levels and worse mobility than those with shorter delay (mean [SD], no change vs. job change vs. permanently disabled): CRP, mg/L: 11.1 (8.3) vs. 17.6 (22.2) vs. 39.7 (46.4); P = 0.034 Modified lumbar Schober test, cm: 4.3 (1.4) vs. 3.2 (1.3) vs. 2.0 (1.5); P < 0.001 Lateral lumbar flexion, cm: 18.2 (10.8) vs. 14.7 (12.7) vs. 7.8 (3.5); P < 0.001 Chest expansion, cm: 5.5 (2.0) vs. 4.5 (2.1) vs. 2.4 (1.5); P < 0.001 Chin-sternum distance, cm: 0.2 (0.8) vs. 1.3 (1.8) vs. 2.0 (2.4); P = 0.001 Tragus-to-wall distance, cm: 0.6 (1.9) vs. 1.2 (2.5) vs. 6.9 (6.2); P = 0.001 Intermalleolar distance, cm: 113.9 (15.3) vs. 105.3 (17.2) vs. 90.6 (21.3); P < 0.001 BASFI: 3.3 (2.1) vs. 4.6 (2.1) vs. 5.2 (2.5); P = 0.005 BASMI: 1.1 (1.1) vs. 2.4 (1.3) vs. 4.3 (2.3); P < 0.001 |
Dincer U, et al. 2008 | AS [111] | < 3 years vs. > 3 years | BASDAI BASFI | No significant differences in BASDAI or BASFI scores |
Slobodin G, et al. 2011 | AxSpA [148] | ≤ 1 vs. 1–5 vs. ≥ 5 | CRP ESR Schober test Finger-to-floor distance Occiput-to-wall distance Chest expansion | Patients with delay of > 1 year had significantly (P = 0.028) greater occiput-to-wall distance (less spinal flexibility) than those diagnosed within 1 year (mean [SD]: ≤ 1 year, 1.5 [5.4] cm; 1–5 years, 3.7 [2.0] cm; ≥ 5 years, 2.4 [5.3]) |
Cayetti LA, et al. 2013 | AS [147] | ≤ 3 vs. > 3 to ≤ 10 vs. > 10 | BASDAI BASFI BASMI BASRI | No substantial impact of delay on functional capacity or radiographic damage |
Economic Burden of Delayed Diagnosis
Study | Patient population [N] | Definition of delay, years | Economic outcome measures | Patient outcomes |
---|---|---|---|---|
Seo MR, et al. 2015 | SpA [105] | ≤ 8 vs. > 8 | Social disabilitiesa | Higher proportion of patients with delay of > 8 years reported social disabilities compared with those with delay of ≤ 8 years, although the difference did not reach statistical significance (28.3 vs. 12.8%; P = 0.06) |
Gunasekera W, et al. 2014 | AS [106] | Continuous | Work disability | Patients who were work disabled had a significantly longer delay than those who were not work disabled (mean, 16.6 vs. 7.8 years; P = 0.005) Risk of being work disabled increased by 6.6% per year of delay (OR, 1.07 [CI, 1.0–1.1]; P = 0.0009) |
Sullivan C, et al. 2014 | AS [92] | 0–4 vs. 5–9 vs. > 10 vs. unknown | TNFi use | No relationship between diagnostic delay and likelihood of TNFi use |
Sullivan C, FitzGerald O. 2011 | AS [59] | < 4 vs. 5–9 vs. > 10 | Employment | Longer delay was associated with greater likelihood of work disability; unemployment rose from 20 to 29% to 41% among those diagnosed in < 4 years, 5–9 years, and > 10 years, respectively |
Mennini FS, et al. 2018 | AxSpA [1084] | 3 years prior to initial SpA diagnosis | Cost (€) of SpA-related specialist visits and treatments | In 3 years prior to SpA diagnosis, patients received an average of 4 specialist services and 4 treatments related to undiagnosed SpA, resulting in an average cost of ≈ €140.90 per patient, corresponding to ≈ €152,767 for study population and ≈ €5,387,972 for Italian population of patients with SpA |
Abdelrahman FI, Mortada M. 2018 | AxSpA [126] | Mean (SD), 11.3 (3.9) vs. 4.6 (2.8) | Healthcare costs Doctor visits Spinal surgery | Patients with longer delay had worse economic outcomes than those with shorter delay (all P < 0.001): Cost of delay period, mean (SD): $9879.30 ($3827.20) vs. $2373.90 ($881.80) No. of doctor visits during delay period, mean (SD): 14.3 (6) vs. 5.6 (3.4) Proportion of patients with unnecessary spinal surgery: 65.4 vs. 34.6% |
Abdul-Sattar A, Abou El Magd S. 2017 | AS [190] | Continuous | Work disability | Patients who were work disabled had significantly longer delay than those who were not work disabled (mean [SD], 8 [2.9] vs. 4 [2.1] years; P < 0.001) Longer delay was associated with greater likelihood of work disability (OR, 2.1 [95% CI, 1.00–3.40]; P = 0.001) |
Cakar E, et al. 2009 | AS [121] | Continuous | Work disability | Patients who were permanently work disabled or changed jobs due to work disability had longer mean (SD) delay (7.8 [6.9] and 7.3 [4.8] years) than those who were not work disabled (3.7 [3.6] years; P = 0.028) |
Grigg SE, et al. 2011 | AS [127] | < 5 vs. 5–10 vs. > 10 | Treatment costs ($) Employability | Estimated cost of treatment prior to diagnosis was > $3000 in 25.6% of patients with < 5 years of delay vs. 44.4% with 5–10 years of delay (P = 0.08) and 67.4% with > 10 years of delay (P = 0.002) Employability was affected in 66.7% of patients with < 5 years of delay vs. 75.6% with 5–10 years of delay (P = 0.37) and 90.7% with > 10 years of delay (P = 0.003) |
Humanistic Burden of Delayed Diagnosis
Study | Patient population [N] | Definition of delay, years | Humanistic outcome measures | Patient outcomes |
---|---|---|---|---|
Martindale J, Goodacre L. 2014 | AS/AxSpA [10] | Continuous | Emotional and social health | In the period between symptom onset and diagnosis (mean [SD], 10.1 [7.3] years; range, 1–20 years), patients experienced negative psychological impact, including desperation, distress, depression, and feeling disheartened; employed patients felt stigmatized by the perception of a “bad back” |
Fitzgerald G, et al. 2017 | AxSpA [564] | < 7 vs. ≥ 7 | Depression | Higher prevalence of depression in patients with delay of ≥ 7 years than those with delay of < 7 years (15.5 vs. 9.1%; P = 0.032) |
Fallahi S, Jamshidi AR. 2016 | AS [163] | Continuous | ASQOL Fatiguea Morning stiffnessb | Delay positively correlated with worse ASQOL scores (r = 0.21; P = 0.008) and morning stiffness (r = 0.21; P = 0.006) |
Cakar E, et al. 2009 | AS [121] | Mean (SD) No change in work: 3.7 (3.6) Work disabled, change in job: 7.3 (4.8) Permanently work disabled: 7.8 (6.9) | Morning stiffness BAS-G SF-36 Beck Depression Inventory | Patients with longer delay had worse mean (SD) scores in physical functioning and general health domains of SF-36 than those with shorter delay Physical functioning: no change, 59.96 (21.99); change in job, 43.14 (23.15); permanently disabled, 51.16 (19.95); P = 0.009 General health: no change, 46.00 (20.90); change in job, 33.67 (20.27); permanently disabled, 22.04 (19.99); P = 0.035 |
Cayetti LA, et al. 2013 | AS [147] | ≤ 3 vs. > 3 to ≤ 10 vs. > 10 | ASQOL | No significant differences in ASQOL scores between groups |
Grigg SE, et al. 2011 | AS [127] | < 5 vs. 5–10 vs. > 10 years | Emotional relief Perception of symptoms Outlook for the future Beck Depression Inventory | Once diagnosed, 69% experienced emotional relief, 76% experienced a positive shift in perception of symptoms, and 66% had an optimistic outlook for the future Delay was not associated with long-term depressed mood as assessed by Beck Depression Inventory scores |