Introduction
Methods
Literature Search
Inclusion and Exclusion Criteria
Data Extraction
Compliance with Ethics Guidelines
Results
Objective | Studya | Number of subjects | Males (%) | Age (years) | Specimens | ||
---|---|---|---|---|---|---|---|
A-RLA | Comparative group(s) | Range | Average | ||||
Etiology of A-RLA vs. responsive LA and/or other arthritis | Strle et al. 2017 [13] | 81 | 60 Antibiotic-responsive LA | Serum and SF | |||
Crowley et al. 2016 [14] | 114 | 58 Healthy controls 91 Antibiotic-responsive LA | Serum, PBMCs, SF | ||||
Strle et al. 2014 [31] | 159 | SF | |||||
Drouin et al. 2013 [19] | 109 | 74 Healthy controls 21 Rheumatoid arthritis 77 Antibiotic-responsive LA | SF and serum | ||||
Strle et al. 2012 [21] | 101 | 76 Antibiotic-responsive LA | 12–79 | PBMCs | |||
Strle et al. 2011 [35] | 12 | 5 Antibiotic-responsive LA | SF | ||||
Kannian et al. 2007 [24] | 41 | 23 Antibiotic-responsive LA | 66 | 13–64 | 41 | Serum | |
Shin et al. 2007 [25] | 35 | 17 Antibiotic-responsive LA | 75 | 12–79 | 38 | SF and tissue | |
Nimmrich et al. 2014 [11]* | 8 | 23 Antibiotic-responsive LA | 37.5 | 11 ± 2 | Serum | ||
Londono et al. 2014 [17] | 14 | 6 Other arthritis | 50 | 11–43 | 16 | SF | |
Vudattu et al. 2011 [34] | 16 | 15 Antibiotic-responsive LA | PBMCs and SF mononuclear cells | ||||
Shen et al. 2010 [22] | 12 | 6 Antibiotic-responsive LA | 67 | 11–54 | 29 | PBMCs and SF mononuclear cells | |
Kannian et al. 2007 [23] | 7 | 6 Antibiotic-responsive LA | 77 | 12–64 | 25 | PBMCs and SF mononuclear cells | |
Lochhead et al. 2017 [12] | 27 | 5 Pre-treatment controls 8 Other arthritis | 69 | 17–76 | 45 | SF | |
Lochhead et al. 2015 [29] | 10 | 6 Antibiotic-responsive LA 5 Other arthritis | SF | ||||
Strle et al. 2011 [27] | 101 | 76 Antibiotic-responsive LA | SF | ||||
Steere et al. 2006 [26] | 71 | 50 Antibiotic-responsive LA | Not specified | ||||
Mechanisms of A-RLA vs. healthy controls | Pianta et al. 2015 [15] | 89 | 52 Healthy controls | Serum, SF | |||
Crowley et al. 2015 [16] | 94 | 57 Healthy controls | Serum, SF | ||||
Vudattu et al. 2013 [18] | 16 | 15 Antibiotic-responsive LA 13 healthy controls | 69 | 12–62 | 29 | Peripheral blood and SF | |
Crowley et al. 2015 [30] | 114 | SF | |||||
Crowley et al. 2014 [32] | Serum | ||||||
Pianta et al. 2014 [33] | SF and serum | ||||||
Katchar et al. 2013 [20] | 15 | 8 Antibiotic-responsive LA 4 Healthy controls | 53 | 12–78 | 29 | Peripheral blood and SF | |
Genetics of A-RLA | Strle et al. 2015 [28] | SF | |||||
Early vs. late manifestations of LD | Uhde et al. 2016 [36] | 11 | 67 Healthy controls | 63.6 | 53 ± 21 | Serum |
Study | Biomarker class | Biomarker(s) | Assay | Summary of results |
---|---|---|---|---|
Strle et al. 2017 [13] | Innate immune cytokine response | CCL3, TNF-α, CXCL9, IL-17F | Luminex assay | A total of 21 mediators associated with innate, T-helper 1 cell and T-helper 17 cell immune responses were assessed in serum and SF IL-17F in serum and CCL2, CCL3, TNF-α and CXCL9 in SF were significantly higher in A-RLA compared with antibiotic-responsive LA |
Crowley et al. 2016 [14] | Immune response in A-RLA | MMP-10 stimulated PBMCs, serum MMP-10, synovial fluid MMP-10, synovial fluid MMP-3 | Bead-based multiplex coupled with Luminex assay | The response was specific to MMP-10-stimulated PBMCs that had a significantly higher T-cell and B-cell reactivity in A-RLA compared with healthy controls and antibiotic-responsive LA |
Pianta et al. 2015 [15] | Cytokine response and expression | T-cell reactivity (IFN-γ response) and IgG response to annexin A2/annexin A2 protein levels in SF and serum | ELISA | Significantly higher response (IFN-γ and IgG) to annexin A2 and elevated annexin A2 protein levels (in SF and serum) among A-RLA compared with healthy controls |
Crowley et al. 2015 [16] | Cytokine response | T-cell reactivity (IFN-γ response) and IgG response to apolipoprotein B-100 and apolipoprotein B-100 in serum | ELISA | Apolipoprotein B-100 protein levels were also significantly higher in serum of A-RLA compared with healthy controls Significantly higher IgG response to apolipoprotein B-100 among A-RLA compared with healthy controls T-cell reactivity (IFN-γ) was borderline significant (p = 0.06) in A-RLA compared with healthy controls |
Strle et al. 2015 [28] | Cytokine response | MMP1, MMP2, MMP3, MMP9, MMP13, IL-6, IL-8, IL-10, TNF, CCL2, CXCL9, CXCL10 from FLS simulated with B. burgdorferi | Luminex assay | A total of 8 MMPs and 21 cytokines and chemokines were assayed in FLS A-RLA exhibited significantly higher levels of IL-6, IL-8, IL-10, TNFα, CCL2, CXCL9, CXCL10 |
Crowley et al. 2014 [32] | Cytokine response | Response of T cell (autoantibody) to MMP-10 | Not specified | Higher numbers of A-RLA patients had robust or autoantibody T-cell responses to MMP-10—compared with antibiotic-responsive LA, healthy controls or rheumatoid arthritis patients |
Strle et al. 2014 [31] | Levels of inflammatory cytokines and chemokines and response to cytokines | Th17-associated mediators and frequency of autoantibody responses to hECGF | Luminex | Higher levels of Th17 associated mediators (e.g., IL-23) and a greater frequency of autoantibody responses to hECGF among A-RLA compared with antibiotic-responsive LA |
Crowley et al. 2014 [32] | Cytokine response | T-cell and B-cell reactivity (IgG anti-ApoB antibodies) to apolipoprotein B-100 | ELISA | Significantly higher frequency of A-RLA had T-cell and B-cell responses to anti-ApoB IgG antibodies compared with healthy controls and patients with EM |
Pianta et al. 2014 [33] | Cytokine response | Anti-annexin A2 IgG autoantibody response in serum | ELISA | Significantly higher autoantibody response in A-RLA compared with healthy controls, but similar to that in antibiotic-responsive LA |
Drouin et al. 2013 [19] | Autoantibody and autoantigen responses | Anti-ECGF IgG autoantibody response in serum and ECGF in serum | ELISA | Significantly higher number of A-RLA had positive autoantibody responses to ECGF compared with healthy controls A-RLA exhibited ECGF autoantibodies more frequently than in antibiotic-responsive LA A-RLA showed significantly higher levels of ECGF in SF compared with antibiotic-responsive LA |
Strle et al. 2012 [21] Strle et al. 2011 [35] | Chemokine and cytokine levels | CXCL9, CXCL10, IL-6, IL-8, IL-10, IL-1β, CCL2, CCL3, CCL4, TNF, IFNγ | Bead-based multiplex assay | CXCL9, CXCL10, IL-6, IL-8, IL-10, IL-1β, CCL2, CCL3, CCL4, TNF, IFNγ were more common in (and in significantly higher levels in the SF of) A-RLA compared with antibiotic-responsive LA |
Kannian et al. 2007 [23] | Antibody response | IgG antibody titers in response to B. burgdorferi antigens in serum | ELISA | In A-RLA, during the first 1–3 months after treatment, antibody response to the VlsE peptide declined while the titers to B. burgdorferi DbpA, OspA and Arp increased Synovial inflammation persisted in A-RLA after infection compared with antibiotic-responsive LA |
Shin et al. 2007 [25] | Chemokines and cytokines levels in response to antibiotic treatment | CXCL8, CXCL9, CXCL10, IL-1β, IL-5, IL-6, CCL2, CCL3, CCL4, TNF, IFNγ | Cytometric bead array | Compared with antibiotic-responsive LA, A-RLA exhibited significantly higher CXCL8, CXCL9, CXCL10, CCL4, IL-6, IL-1β, TNF and IFNγ during the antibiotic treatment period and higher CXCL9, CXCL10, IL-5, IL-1β, CCL2, CCL3 and CCL4 following the treatment |
Uhde et al. 2016 [36] | Acute phase reactants | CRP and amyloid A | ELISA | Significantly higher CRP but not amyloid A in A-RLA compared with healthy controls |
Nimmrich et al. 2014 [11] | Protein expression | p58, OspC, P100, VlsE, P39, Ospa and p18 | Western blot | Significantly higher IgG p58 and OspC expression—but not P100, VlsE, P39, Ospa and p18—in A-RLA compared with antibiotic-responsive LA |
Vudattu et al. 2013 [18] | Leukocytes | Monocytes, CD4+ T cells, in peripheral blood or SF | Flow cytometry | Compared with healthy controls, A-RLA exhibited higher levels of monocytes and CD4+ T cells in peripheral blood Compared with antibiotic-responsive LA, A-RLA had lower CD4+ T cells in SF |
Katchar et al. 2013 [20] | Lymphocytes | CD3+ T cells in peripheral blood, CD56 bright NK cells and Vα24+ iNKT cells in SF | Flow cytometry | A-RLA had lower CD3+ T cells in peripheral blood compared with healthy controls and lower CD56 bright NK cells and Vα24+ iNKT cells in SF compared with antibiotic-responsive LA |
Vudattu et al. 2011 [34] | Lymphocytes and phenotypes of lymphocytes | CD4+ T cells and expression of GITR and OX40 receptors | Flow cytometry | Increased CD4+ T cells and GITR and OX40 receptors expression in A-RLA compared with antibiotic-responsive LA |
Shen et al. 2010 [22] | Phenotypes of lymphocytes | IL-4+CD4+Th2 cells, IL-17+CD4+ T cells, FoxP3+Treg cells | Flow cytometry | Significantly higher numbers of IL-4+CD4+Th2 cells, IL-17+CD4+T cells and FoxP3+Treg cells were found in A-RLA compared with antibiotic-responsive LA |
Kannian et al. 2007 [23] | Lymphocytes | OspA161–175-specific T cells | Flow cytometry | No significant differences in OspA161–175-specific T-cell frequencies or proliferation responses between A-RLA and antibiotic-responsive LA |
Londono et al. 2014 [17] | Histologic findings | Lining layer thickness, global cellular infiltration, lymphoid aggregates, obliterative macrovascular lesions | Histologic analysis (tissue staining) | Lining layer thickness, global cellular infiltration, lymphoid aggregates, obliterative macrovascular lesions were all more common in A-RLA compared with other arthritis cases |
Study | Biomarker class | Biomarker(s) | Assay | Summary of results |
---|---|---|---|---|
Lochhead et al. 2017 [12] | miRNA | miR-146a, miR142, miR17, miR-155, miR-223, miR20a, let-7a, let-7c | PCR | miR-146a, miR142, miR17, miR-155, miR-223 and miR20a were higher in post- vs. pre-antibiotic treated A-RLA miR-146a, miR142, miR17, miR-155, miR-223, miR20a, let-7a and let-7c were higher in A-RLA compared with osteoarthritis |
Lochhead et al. 2015 [29] | miRNA (extracellular) | miR-146a, miR-155 (inflammatory signature), miR-30fam (vascularization signature), miR223, miR142 | qPCR | miR-146a, miR-155, miR-223 and miR-142 were higher in A-RLA compared with antibiotic-responsive LA miR-146a, miR-155, miR-30fam, miR223 and miR-142 were upregulated in A-RLA compared with osteoarthritis patients |
Strle et al. 2015 [28] | mRNA expression | SOCS3 mRNA expression in cells with 1805GG polymorphism in TLR1 | QuantiGene and whole-genome RNASeq | Altered SOCS3 mRNA expression in A-RLA compared with antibiotic-responsive LA, i.e., greater inflammatory responses |
Strle et al. 2011 [35] | SNPs | Frequency of 1805GG polymorphism in TLR1 gene | PCR | Frequency of the 1805GG polymorphism was lower in A-RLA compared with antibiotic-responsive LA |
Steere et al. 2006 [26] | HLA typing and binding to OspA | HLA-DRB1-DQA1-DQB1/DRB1 allele frequency | High-resolution molecular HLA typing | HLA-DRB1-DQA1-DQB1 haplotype frequencies were similar between A-RLA and responsive LA Larger number of A-RLA patients showed binding to OspA compared with antibiotic-responsive LA |
Biomarker class | Biomarker | Specimens |
---|---|---|
Inflammatory markers | IL-6, IL-8, IL-10, IL-1β, IL-23, IL-17F, TNFα, IFNγ, CXCL9, CXCL10, CCL2, CCL3, CCL4, CRP | Serum and synovial fluids |
Immunity-related markers | miR-146a, miR-155, miR-223 and miR-142, CD4+ T-cells, GITR receptors, OX40 receptors, IL-4+ CD4+ Th2 cells, IL-17+CD4+ T-cells and FoxP3+Treg cells | Peripheral blood and synovial fluids |
Other markers | Annexin A2, hECGF | Serum and synovial fluids |