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Vascular dysfunction in juvenile idiopathic arthritis: a systematic review and meta-analysis

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Abstract

We performed a systematic review and meta-analysis of studies evaluating vascular function in patients with JIA. Relevant literature published from 1st January 1965 to 1st March 2022 was searched systematically utilizing PubMed, Web of Science, and Embase databases. Observational studies were included—patients with JIA (classified according to the International League of Associations for Rheumatology criteria) were included as cases (study population) and age/sex-matched healthy participants as controls (comparator group). Outcome measures were differences in non-invasive parameters of vascular function. Online Population, Intervention, Comparison, Outcomes Portal was used for deduplication of studies and data extraction. Review Manager, Comprehensive Meta-analysis, and Meta-Essential softwares were used for data synthesis/analysis (encompassing data pooling and evaluation of heterogeneity and publication bias). Newcastle–Ottawa Scale and GRADEpro GDT software were utilized to assess study quality and certainty of evidence, respectively. Of 338 citations, 17 observational studies with 1423 participants (cases = 757, controls = 666) were included. Carotid intima-media thickness (CIMT) was higher [mean difference (MD) 0.02 mm {95% confidence interval (CI) 0.01–0.04}, p = 0.0006, I2 = 69%] in patients with JIA. Besides, decreased flow-mediated dilatation (FMD) [MD − 2.18% {95%CI − 3.69– − 0.68}, p = 0.004, I2 = 73%] was also observed. Results of studies assessing pulse wave velocity or arterial stiffness could not be pooled due to significant methodological variations. A ‘very low’ certainty of evidence suggests the presence of vascular dysfunction in JIA. Future longitudinal studies are required to determine whether altered CIMT and FMD in patients with JIA translate to an enhanced risk of (adverse) clinical cardiovascular events. PROSPERO (CRD42022323752).

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Relevant data utilized in the preparation of this manuscript are provided in the main manuscript and supplementary tables/figures. Additional data underlying this article will be shared on reasonable request to the corresponding author.

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Author notes

  1. Pratap Kumar Patra and Aaqib Zaffar Banday contributed equally and qualify as joint first authors.

Authors and Affiliations

  1. Department of Pediatrics, Allergy Immunology Unit, All India Institute of Medical Sciences (AIIMS), Patna, 801105, India

    Pratap Kumar Patra & Pakkiresh Reddy

  2. Rheumatology Division, Kashmir Clinics Group, Balgarden, Srinagar, India

    Aaqib Zaffar Banday

  3. Clinical Immunology and Rheumatology Division, Department of Pediatrics, Khyber Medical Institute, Nowpora, Srinagar, India

    Aaqib Zaffar Banday

  4. Department of Anatomy, AIIMS, Patna, India

    Adil Asghar

  5. Department of Microbiology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India

    Rahila Nisar

  6. Department of Pediatrics, AIIMS, Bhubaneshwar, India

    Rashmi Ranjan Das

  7. Advanced Center for Immunology and Rheumatology, Om Hospital and Research Center, Katmandu, Nepal

    Dharmagat Bhattarai

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Contributions

PKP: conception of idea and design of the study; acquisition, analysis, and interpretation of data; drafted, edited, and critically revised the manuscript. AZB, RN: acquisition, analysis, and interpretation of data; drafted, edited, and critically revised the manuscript. AA, RRD: designed the study; acquisition, analysis, and interpretation of data; edited and critically revised the manuscript. PR, DB: acquisition, analysis, and interpretation of data; edited and critically revised the manuscript. All co-authors approve the final version of the manuscript and take full responsibility for the integrity and accuracy of all aspects of the study.

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Correspondence to Pratap Kumar Patra.

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Supplementary Information

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296_2022_5255_MOESM1_ESM.tif

Supplementary file1 (TIF 199 KB) Supplementary Fig. S1: Funnel plots assessing the publication bias for various outcome measures of vascular function. A: No publication bias was observed for studies assessing CIMT in patients with JIA as compared to controls. The corresponding p-values of Egger regression and Begg & Mazumdar tests were 0.2 and 0.6, respectively; B: lack of publication bias was also observed for studies evaluating FMD in patients with JIA as compared to controls. The corresponding p-values of Egger regression and Begg & Mazumdar tests were 0.6 and 0.5, respectively.

296_2022_5255_MOESM2_ESM.tif

Supplementary file2 (TIF 134 KB) Supplementary Fig. S2: Regression plots assessing the correlation between heterogeneity and individual covariates. A: In studies comparing CIMT of patients with JIA to controls, age at enrolment significantly correlated (p=0.004) with the underlying heterogeneity; B: although none of the covariates included associated significantly with heterogeneity in studies evaluating FMD, levels of serum triglycerides showed a trend towards statistical significance (p=0.08).

296_2022_5255_MOESM3_ESM.tif

Supplementary file3 (TIF 2181 KB) Supplementary Fig. S3: Forest plots comparing CIMT between various subgroups of patients with JIA. A: Patients with sJIA and non-systemic JIA (including oligoarthritis and polyarthritis) had comparable CIMT; B: similar CIMT was observed in patients with oligoarthritis and polyarthritis; C: no significant difference in CIMT was noted when patients with active disease were compared to patients with inactive disease.

296_2022_5255_MOESM4_ESM.tif

Supplementary file4 (TIF 1496 KB) Supplementary Fig. S4: Forest plots comparing FMD between various subgroups of patients with JIA. A: Patients with sJIA and non-systemic JIA (including oligoarthritis and polyarthritis) had comparable FMD; B: similar FMD was observed in patients with oligoarthritis and polyarthritis.

296_2022_5255_MOESM5_ESM.tif

Supplementary file5 (TIF 782 KB) Supplementary Fig. S5: Similar CIMT was noted in patients with JIA and controls in the studies wherein the final measure of intima-media thickness also included bilateral carotid bulbs plus/minus bilateral internal carotid arteries (in addition to common carotid arteries).

296_2022_5255_MOESM6_ESM.tif

Supplementary file6 (TIF 764 KB) Supplementary Fig. S6: Decreased FMD is noted in patients with JIA when results of studies with similar levels of traditional cardiovascular risk factors in the 2 groups (patients and controls) are pooled.

Supplementary file7 (DOCX 28 KB) Supplementary Table S1: PRISMA 2020 for abstracts checklist.

Supplementary file8 (DOCX 40 KB) Supplementary Table S2: PRISMA 2020 for main manuscripts checklist.

296_2022_5255_MOESM9_ESM.docx

Supplementary file9 (DOCX 30 KB) Supplementary Table S3: Protocol(s) used in various studies to evaluate carotid intima-media thickness in patients with JIA.

296_2022_5255_MOESM10_ESM.docx

Supplementary file10 (DOCX 36 KB) Supplementary Table S4: Quality of the studies included according to the Modified Newcastle-Ottawa Scale.

296_2022_5255_MOESM11_ESM.docx

Supplementary file11 (DOCX 17 KB) Supplementary Table S5: Grade of evidence of altered CIMT and FMD in patients with JIA as compared to controls.

296_2022_5255_MOESM12_ESM.docx

Supplementary file12 (DOCX 35 KB) Supplementary Table S6: Disease and treatment characteristics of studies evaluating vascular function in patients with juvenile idiopathic arthritis in comparison to controls. Traditional cardiovascular risk factors (and related parameters) that were significantly different between cases and controls have also been detailed briefly.

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Patra, P.K., Banday, A.Z., Asghar, A. et al. Vascular dysfunction in juvenile idiopathic arthritis: a systematic review and meta-analysis. Rheumatol Int 43, 33–45 (2023). https://doi.org/10.1007/s00296-022-05255-5

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