Non-antibody serological markers in the preclinical phase of RA
| Author, Year | Study population | Cases (n) | Progression to arthritis (%) | Median duration from study entry to diagnosis of arthritis, months (IQR) | Median duration of follow-up, months (IQR) | Measured factors | Main result |
| Proteins | |||||||
| Bos et al, 201022 | ACPA+ and/or RF+ arthralgia (secondary care) | 147 | 29 (20) | 11 (5–17) | 28 (19–39) | CRP levels | CRP levels were similar in patients with and without arthritis development (3.0, IQR 1.1–4.7; and 2.3, IQR 0.9–5.0; P=0.81, respectively). |
| Limper et al, 201236 | ACPA+ and/or RF+ arthralgia (secondary care) | 137 | 35 (26) | 11 (3.7–18) | 21 (6–48) | hsCRP, PCT and SPLA2 levels, and TNF-α, IL-6, IL-12p70, IL-10 and IFN-γ | Biomarker levels were not significantly different in patients with and without progression to arthritis during follow-up. |
| van de Stadt et al, 201237 | ACPA+ and/or RF+ arthralgia (secondary care) | 348 | 116 (33) | 12 (6–23) | 24 (14–49) | Total cholesterol, HDLc, LDLc, triglycerides, apoA1 and apoB | After correction for ACPA only ApoA1 was predictive of arthritis development (HR 0.5, 95% CI 0.3 to 0.9). For HDLc, a trend was observed (HR first vs second and third tertiles 0.7, 95% CI 0.5 to 1.0). |
| de Smit et al, 201454 | ACPA+ and/or RF+ arthralgia (secondary care) | 289 | 94 (33) | 12 (6–20) | 30 (13–49) | IgA, IgG and IgM antibody levels against Porphyromonas gingivalis | Anti-P. gingivalis antibody levels at baseline were not elevated in patients with progression to arthritis compared with patients without progression. |
| Rakieh et al, 201527 | ACPA+ persons with aspecific musculoskeletal symptoms (primary and secondary care) | 100 | 50 (50) | 7.9 (0.1–52) | 20 (0.1–69) | hsCRP levels | CRP level at baseline was not associated with arthritis development (uncorrected HR 1.3, 95% CI 0.7 to 2.4). PPV for arthritis development: 56%. |
| Rombouts et al, 201531 | ACPA+ arthralgia (secondary care) | 183§ | 105 (57) | 12 (6–24) | 35 (21–52) | ESR | ESR was increased prior to the diagnosis of RA (arthralgia at baseline: median 15.0 mm/hour (IQR 7.0–25); RA at diagnosis: 25 mm/hour (IQR 19–33)). |
| Janssen et al, 201630 | ACPA+ and/or RF+ arthralgia (secondary care) | 34 | 14 (41) | 17 (5–35) | 40 (24–43) | CRP levels and ESR | At study entry CRP levels and ESR were comparable between patients with and without progression to arthritis. |
| van Steenbergen et al, 201624 | Clinically suspect arthralgia (secondary care) | 150* | 30 (20) | 1.7 (0.8–4.1) | 17 (9–24) | CRP levels | CRP level was associated with arthritis development, independent of other clinical factors and MRI-detected inflammation (HR 1.1, 95% CI 1.0 to 1.1). PPV for arthritis development: 32%. |
| van Beers-Tas et al, 201638 | ACPA+ and/or RF+ arthralgia (secondary care) | 144 | 43 (30) | 15 (0–60) | 60 (1–60) | 14-3-3η | 14-3-3η was associated with arthritis development in patients with seropositive arthralgia, but when corrected for ACPA and RF 14-3-3η did not predict onset of arthritis. PPV of 14-3-3-η for arthritis development: 86%. |
| Chalan et al, 201634 | ACPA+ and/or RF+ arthralgia (secondary care) | 27 | 11 (41) | 8 (1–32) | Patients with non-progressing arthralgia: 26 (6-33) | 25 serum immune markers: IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12 (p40/p70), IL-13, IL-15, IL-17, IFN-α, IFN-γ, GM-CSF, TNF-α, IL-1RA, IL-2 R, Eotaxin (CCL11), IL-8, IP-10 (CXCL10), MCP-1 (CCL2), MIG (CXCL9), MIP-1α (CCL3), MIP-1β (CCL4), Rantes (CCL5) | Trends for increase in IL-5, MIP-1β, IL-1RA and IL-12 in patients with arthralgia with progression to arthritis. AUC for IL-5 was 0.8 (95% CI 0.6 to 1.0). ESR and CRP were not significantly different in patients with and without progression to RA. |
| Zufferey et al, 201735 | RF and ACPA polyarthralgia of >6 weeks’ duration (secondary care) | 80 | 9 (11) | NP | 18 (7)† | CRP levels | CRP level was not predictive of RA in univariable or multivariable regression analysis (OR 3.0, 95% CI 0.4 to 24, corrected for gender and US score). PPV of CRP for development of arthritis: 22% |
| PBMCs and expression of cell surface markers | |||||||
| Janssen et al, 201630 | ACPA+ and/or RF+ arthralgia (secondary care) | 34 | 14 (41) | 17 (5–35) | 40 (24–43) | Treg number and subsets | Treg number and subsets were comparable in patients with and without progression to arthritis during follow-up. |
| Lübbers et al, 201551 | ACPA+ and/or RF+ arthralgia (secondary care) | 155 | 44 (38) | 8 (5–13) | 23 (12–30) | B cell signature, comprising CD19, CD20, CD79α, CD79β | Combination of low B cell score and high type I IFN signature predicts arthritis development in seropositive arthralgia. AUC for B cell score combined with ACPA and RF was 0.9 (95% CI 0.8 to 1.0) in IFNhigh group and 0.7 (95% CI 0.6 to 0.8) in IFNlow group. PPV of IFNhigh Bcelllow score for development of arthritis: 60%. |
| Lübbers et al, 201650 | ACPA+ and/or RF+ arthralgia (secondary care) | 113 | 40 (35) | 13 (7.4–22) | 27 (19–42) | Absolute number of CD14+ monocytes, CD4+, CD8+, CD56+ T cells (CD3+), CD80+, CXCR3+, CD27+ B cells (CD19+) and CD16+ CD56+ CD3− NK cells | Decreased CD8+ T cells and memory B cells in patients who developed arthritis. |
| Hunt et al, 201649 | ACPA+ persons with aspecific musculoskeletal symptoms (primary and secondary care) | 103 | 48 (47) | 63% progressed within 12 months | 18 (0.1–80)‡ | Naïve T cells, inflammation-related cells and Tregs | T cell subset dysregulation in ACPA+ individuals predates the onset of inflammatory arthritis, predicts risk and faster progression to inflammatory arthritis. PPV for T cell subset combined with clinical factors was 60%. PPV of clinical model alone was 50%. |
| Gene expression total blood | |||||||
| van Baarsen et al, 201055 | ACPA+ and/or RF+ arthralgia (secondary care) | 109 | 20 (18) | 7 (4–15) | 30 (22–39) | Gene expression profile | Signatures associated with arthritis development were involved in IFN-γ-mediated immunity, haematopoiesis and chemokine/cytokine activity. |
| Limper et al, 201236 | ACPA+ and/or RF+ arthralgia (secondary care) | 137 | 35 (26) | 11 (3.7–18) | 21 (6–48) | mRNA expression levels of 21 inflammatory genes | Biomarker levels were not significantly different in patients with and without progression to arthritis during follow-up. |
| Lübbers et al, 201356 | ACPA+ and/or RF+ arthralgia (secondary care) | 115 | 44 (38) | 8 (5–13) | 23 (12–30) | Expression level of 7 type I IFN response genes: IFI44L, IFI6, IFIT1, MXA, OAS3, RSAD2, EPSTI | HR for development of arthritis was 2.4 (95% CI 1.3 to 4.5) for IFNhigh individuals, corrected for ACPA and RF. AUC for IFN-score combined with ACPA and RF was 0.8 (95% CI 0.7 to 0.9). PPV of ACPA/RF combined with IFN score for development of arthritis was 65%. |
| Tak et al, 201752 | Seropositive individuals (ACPA and/or RF) at risk for RA | 71 | 26 (37) | NP | Test cohort: no arthritis 69 (42–78), arthritis 15 (0–65) Validation cohort: at least 36 months | Dominant BCR clones (BCR signals representing ≥0.5% of the repertoire) in PB and synovial tissue | Presence of ≥5 dominant BCR clones in PB was associated with arthritis development (validation cohort: RR 6.3, 95% CI 2.7 to 15). PPV of ≥5 dominant BCR clones for development of arthritis: 72% in test cohort and 83% in validation cohort. |
Patients in refs 22 31 36 37 52 54 55, in refs 30 34, in refs 27 49 and in refs 38 50 51 56 are derived from the same cohort. Studies depicted in grey have provided absolute risks.
*One patient that developed gout during follow-up was excluded from analyses.
†Mean (SD).
‡Median (range).
§Patients in this study were selected based on high ACPA serum level (median 419 U/mL, IQR 131.0–1216.0).
ACPA, anticitrullinated protein antibodies; apo, apolipoprotein; AUC, area under curve; BCR, B cell receptor; CD, cluster of differentiation; CRP, C reactive protein; EPSTI, epithelial stromal interaction; ESR, erythrocyte sedimentation rate; GM-CSF, granulocyte macrophage colony-stimulating factor; HDLc, high density lipoprotein cholesterol; (hs)CRP, (high sensitivity) C reactive protein; IFN, interferon; IFI44L, interferon-induced protein 44 like; IFI6, interferon alpha-inducible protein 6; IFIT1, interferon induced protein with tetratricopeptide repeats 1; IL, interleukin; LDLc, low density lipoprotein cholesterol; MCP-1, monocyte chemoattractant protein-1; MIG, monokine induced by gamma interferon; MIP, macrophage inflammatory protein; MXA, myxovirus resistance protein A; NK cells, natural killer cells; NP, not provided; OAS3, 2'−5'-oligoadenylate synthetase 3; PB, peripheral blood; PBMC, peripheral blood mononuclear cell; PCT, procalcitonin; PPV, positive predictive value; RA, rheumatoid arthritis; RANTES, regulated on activation, normal T cell expressed and secreted; RF, rheumatoid factor; RR, relative risk; RSAD2, radical s-adenosyl methionine domain containing 2; SPLA2, secretory phospholipase A2; TNF-α, tumour necrosis factor-α; Treg, regulatory T cell; US, ultrasound.