Abstract
Objectives:
To analyse the accuracy of plasma calprotectin in patients with rheumatoid arthritis (RA) receiving monoclonal antibodies against IL-6 receptors (anti-rIL-6) or JAK inhibitors (JAKis) in detecting ultrasound (US) synovitis and compare it with acute phase reactants [high-sensitivity C-reactive protein (hs-CRP) and ESR].
Methods:
An observational cross-sectional study of RA patients receiving anti-rIL-6 (tocilizumab or sarilumab) or JAKi, (baricitinib or tofacitinib) was made. Plasma calprotectin for the diagnosis of US synovitis [synovial hypertrophy grade (SH) ⩾ 2 plus power Doppler signal (PD) ⩾ 1] was analysed using receiver operating characteristic curves (ROCs). The performance of ESR and hs-CRP was also studied. The three ROC curves were compared to determine which had the highest discriminatory power. Associations between plasma calprotectin and US scores were made using correlation analysis.
Results:
Sixty-three RA patients were included. Mean plasma calprotectin levels were significantly higher in patients with US synovitis than in those without (0.89 ± 0.85 vs 0.30 ± 0.12 μg/ml; p = 0.0003). A moderate correlation between calprotectin and all US scores (HS score Rho = 0.479; PD score Rho = 0.492; and global score Rho = 0.495) was found. The discriminatory capacity of plasma calprotectin showed an AUC of 0.795 (95% CI: 0.687–0.904). The AUC of hs-CRP and ESR was 0.721 and 0.564, respectively. hs-CRP serum levels showed a low positive correlation with the three US scores (Rho < 0.40). After analysis according to the drugs administered, the correlation disappeared in patients receiving anti-rIL-6.
Conclusion:
Plasma calprotectin may be a sensitive biomarker of synovial inflammation in RA patients treated with anti-rIL-6 or JAKi.
Keywords: acute phase proteins, biomarkers, leukocyte L1 antigen complex (calprotectin), rheumatoid arthritis, ultrasonography
Introduction
The prognosis of rheumatoid arthritis (RA) has significantly improved in recent decades. In patients who do not achieve the therapeutic goal (remission or low disease activity) with a first strategy using conventional synthetic disease-modifying antirheumatic drugs (DMARDs), e.g. methotrexate, a second strategy using targeted therapies, biologics, or selective Janus kinase inhibitors (JAKi) is recommended. 1 Monoclonal antibodies against interleukin (IL)-6 receptors (anti-rIL-6) (tocilizumab and sarilumab) and JAKi (tofacitinib, baricitinib and, more recently, upadacitinib) are included in this strategy, with significant improvements in clinical and radiographic outcomes.2,3 It has been shown that both families of targeted therapies have a profound impact on the acute phase response, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), due to inhibition of hepatocyte stimuli via IL-6.4,5 Acute phase reactants (APRs) form part of the composite activity indices [e.g. Disease Activity Score (DAS) and Simplified Disease Activity Index (SDAI)] used to measure inflammatory activity in RA and may lead to an overestimate of the clinical response when using these targeted drugs. 6
Calprotectin is a heterodimeric complex of two S100 calcium-binding myeloid-related proteins (MRP8 [or S100A8] and MRP14 [or S100A9]) which is released from cells of the innate immunity, such as neutrophils or monocytes, which have proinflammatory activities and act as endogenous-associated molecular patterns via Toll-like receptor activation. 7 Calprotectin is strongly expressed in rheumatoid synovial membrane. 8 Recently, serum and plasma calprotectin have been found to be sensitive markers of inflammatory activity in RA patients 9 and have been associated with radiographic damage, 10 as a biomarker of clinical response to antirheumatic drugs 11 and as a predictive factor for disease relapse. 12
Joint ultrasound (US) is a validated imaging technique for synovitis evaluation in RA, with a higher sensitivity than the clinical examination in detecting active synovitis. 13 A significant proportion of patients in clinical remission may exhibit active synovitis on US. 14 Recent studies have shown that calprotectin is more associated closely than APR with US synovitis in RA, even in patients in remission or with low disease activity.15,16
We have shown that in RA patients treated with tocilizumab, serum calprotectin but not serum CRP correlates with disease activity, 17 a finding also observed by other authors. 18 To our knowledge, there are no studies on calprotectin as a biomarker of US synovitis in RA patients treated with anti-rIL-6 or JAKi. The objective of the study was to analyse the accuracy of plasma calprotectin in patients with RA receiving anti-rIL-6 or JAKi in detecting US synovitis and compare it with traditional APR (CRP and ESR). We hypothesized that calprotectin has a higher discriminatory capacity than APR in detecting US synovitis in these patients.
Methods
Design and study population
An observational cross-sectional study of RA patients (ACR/EULAR 2010 criteria) 19 from our arthritis unit receiving anti-IL-6 receptor monoclonal antibodies (tocilizumab or sarilumab) or JAKi (baricitinib or tofacitinib) for ⩾3 months who were consecutively included. Patients were included on the day of the scheduled routine follow-up visit from September 2020 to September 2021. Patients were included regardless of disease activity status, previous DMARDs (including biological therapies or JAKi), and concomitant treatment (methotrexate or others). Patients who, at the study visit presented signs of active infection or other clinical conditions that, in the opinion of the investigator, could modify the results of CRP, ESR, or calprotectin determinations were excluded. Demographic data, disease duration, autoantibody status (ACPA/RF), radiological data (erosive disease), previous biologic therapy, and concomitant therapy were collected.
Measurement of clinical disease activity
All patients underwent a clinical assessment, including 28 swollen and tender joint counts (28-SJC and 28-TJC) and physician and patient global assessment (PhGA and PGA) with visual analogue scales (0–100 mm). Disease activity indices were subsequently calculated (DAS28, SDAI, and CDAI). In addition, participants also were asked to complete two questionnaires: the Health Assessment Questionnaire (HAQ) and the Routine Assessment of Patient Index Data 3 (Rapid3).
Assessment of blood biomarkers
Blood samples were obtained in the clinical evaluation. ESR was measured using the Westergren method (NV < 20 mm/h), and high-sensitivity C-reactive protein (hs-CRP) using an immunoturbidimetric method measured by Siemens Atellica® Solution (lowest detection limit of 0.02 mg/dl; NV < 0.4 mg/dl). Calprotectin plasma levels were determined using an ELISA Test Kit [CALPROLAB ALP (CALPRO), Menarini Diagnósticos S.A.] according to the manufacturer’s protocol. Briefly, 100 µl of each standard, control, and diluted 1:20 sample in duplicate wells were incubated at room temperature for 40 min; three washings were made, 100 µl of the conjugated enzyme was added, and plates were incubated at room temperature for 40 min. After three washes and the addition of the enzyme-substrate, the optical density values at 405 nm were determined using an ELISA reader. To reduce variations in calprotectin determination, the whole procedure was performed in a Triturus autoanalyzer; the coefficients of variation were 5% within and 13% between assays.
Imaging biomarkers: US score
Sonographic assessments were carried out using high-sensitivity US equipment (MyLab9®; Esaote, Genoa, Italy), with a longitudinal probe, frequency range from 10 to 14 MHz and a pulse repetition frequency between 800 and 900 Hz. Joint musculoskeletal US findings were defined according to published Outcome Measures in Rheumatoid Arthritis Clinical Trial (OMERACT) definitions. 20
A single experienced sonographer (AP), who was blinded to the results of the clinical joint examination, evaluated 11 joints and tendons of each hand (including the proximal interphalangeal joints, metacarpophalangeal joints, and wrists) for synovial hypertrophy (SH) and intra-articular power Doppler (PD) signalling according to EULAR guidelines. 21 SH and PD signals were graded using a four-grade semi-quantitative scoring system (0 = no, 1 = mild, 2 = moderate, and 3 = severe) according to the methodology of Szkudlarek et al. 22 The highest SH and PD grade detected during the scans was adopted as representative of each joint, respectively. We also evaluated synovitis in symptomatic joints outside the hands and graded it using the methodology of Szkudlarek et al. 22
By summing the scores for elementary lesions in each joint, we calculated the PD score (sum of PD scores in all joints, range 0–66), the SH score (sum of SH scores in all joints, range 0–66) and the global score (sum of the PD and SH scores, range 0–132). The score does not include joints outside the hands. To ensure a stringent definition of US synovitis, only patients with SH grade ⩾ 2 plus PD signal (⩾1) were classified as having active synovitis. 23
Statistical analysis
Continuous data were presented as the mean (SD) and categorical variables as absolute frequencies with percentages. Groups were compared using parametric or nonparametric tests according to the distribution of the variables.
The performance of calprotectin in the diagnosis of US synovitis was analysed using receiver operating characteristic curves (ROC) with US synovitis yes/no (yes: SH grade ⩾ 2 plus PD signal ⩾ 1) as the gold standard. The ROC curves made it possible to identify the best cut-off point in terms of sensitivity, specificity, and likelihood ratios, and to calculate the area under the curve (AUC) as a measure of the overall discriminative power. The performance of ESR and hs-CRP was also studied, and the three ROC curves were compared to determine which of the three parameters had the highest discriminatory power for the diagnosis of synovitis.
Correlation analysis (Spearman’s correlation coefficient) was used to assess the association between plasma calprotectin and US scores (PD score, SH score, and global score). The analysis was made using STATA version 12 (STATA Corp, College Station, TX, USA).
The study was conducted in accordance with the Declaration of Helsinki and was approved by the Clinical Research Ethics Committee of the Hospital Clinic of Barcelona (Reg. HCB20210783). Written informed consent was obtained from all patients before study enrolment and patients were de-identified. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. 24
No specific funding was received from any bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this article.
Results
Demographic, clinical, and therapeutic characteristics
Although the initial sample consisted of 78 patients, US studies were performed in 63 (42 receiving anti-rIL-6 and 21 JAKi), which was the final sample included in the study. Ninety-two percent of patients were female with a mean age of 56 (±12) years. Mean disease duration was 15 (±8.9) years, 90.5% were seropositive (RF and/or ACPA) and 75.8% had erosive disease. In general, disease activity was low, with a median CDAI value of 11.3 (±8.7). DAS28 remission was observed in 29 patients (46%). The mean duration of drug therapy (anti-rIL-6 or JAKi) was 45 (±42.4) months.
Patient with US synovitis had a significantly higher prevalence of radiographic erosive disease and a trend to a higher disease duration. As expected, higher median values of the disease activity composite index were observed in patients with US synovitis than in those without, although the difference was not significant measured by DAS28. Furthermore, remission rates were higher in patients without US synovitis. No differences were observed according to the drugs used (anti-rIL-6 or JAKi; Table 1).
Table 1.
Demographic, clinical and laboratory characteristics of patients with RA (N = 63). Demographic, clinical and treatment variables, and biomarkers of patients classifying according to ultrasound activity [ultrasound synovitis in ⩾1 joint (SH ⩾ 2 + PD ⩾ 1)].
| Total (n = 63) | No US synovitis (n = 17) | With US synovitis (n = 46) | P value | |
|---|---|---|---|---|
| Age, years (mean ± SD) | 55.9 ± 11.8 | 51.9 ± 12.5 | 57.4 ± 11.3 | 0.159 |
| Disease duration, years (mean ± SD) | 15.0 ± 8.9 | 11.1 ± 6.0 | 16.5 ± 9.4 | 0.051 |
| Female, n (%) | 58 (92.1%) | 16 (94.1%) | 42 (91.3%) | 0.590 |
| Seropositive (RF/ACPA), n (%) | 57 (90.5%) | 15 (88.2%) | 42 (91.3%) | 0.657 |
| Erosions, n (%) | 47 (75.8%) | 9 (56.2%) | 38 (82.6%) | 0.034 |
| Extraarticular manifestations, n (%) | 22 (34.9%) | 4 (23.5%) | 18 (39.1%) | 0.373 |
| Concomitant sDMARDs, n (%) | 29 (48.3%) | 8 (50.0%) | 21 (47.7%) | 0.876 |
| Concomitant glucocorticoids, n (%) | 29 (46.0%) | 7 (41.2%) | 22 (47.8%) | 0.638 |
| Prednisone dose (mg/day), (mean ± SD) | 4.2 ± 2.4 | 4.3 ± 1.2 | 4.1 ± 2.7 | 0.451 |
| Treatment group | 0.688 | |||
| • IL-6 inhibitor (anti-rIL-6) • JAK inhibitor (JAKi) |
42 (66.7%) 21 (33.3%) |
12 (70.6%) 5 (29.4%) |
30 (65.2%) 16 (34.8%) |
|
| Targeted (anti-rIL-6 or JAKi) treatment duration, (mean ± SD) month | 45.9 ± 42.4 | 48.8 ± 46.8 | 44.8 ± 41.2 | 0.846 |
| Laboratory | ||||
| Glomerular filtration rate; ml/mil (mean ± SD) | 82.88 (12.20) | 86.18 (5.87) | 83.20 (11.99) | 0.331 |
| Plasma calprotectin (µg/mL) | 0.73 ± 0.78 | 0.30 ± 0.12 | 0.89 ± 0.85 | 0.0003 |
| ESR mm (mean ± SD) | 14.4 ± 22.3 | 7.8 ± 4.2 | 16.9 ± 25.6 | 0.474 |
| hs-CRP (mean ± SD) mg/dL | 0.21 ± 0.36 | 0.05 ± 0.08 | 0.27 ± 0.41 | 0.007 |
| Disease Activity | ||||
| 28 SJC (mean ± SD) | 3.7 ± 5.4 | 2.8 ± 4.1 | 4.1 ± 5.8 | 0.442 |
| 28 TJC (mean ± SD) | 1.4 ± 1.9 | 0.1 ± 0.3 | 1.9 ± 2.1 | <0.0001 |
| PGA (mean ± SD) | 3.6 ± 2.1 | 3.4 ± 2.4 | 3.7 ± 2.0 | 0.408 |
| PhGA (mean ± SD) | 2.6 ± 1.8 | 1.3 ± 1.3 | 3.0 ± 1.7 | 0.0003 |
| VAS pain (mean ± SD) | 3.8 ± 2.4 | 3.5 ± 2.6 | 3.9 ± 2.4 | 0.508 |
| DAS28 (mean ± SD) | 3.0 ± 1.3 | 2.5 ± 1.1 | 3.2 ± 1.4 | 0.070 |
| • Remission, n (%) a | 29 (46.03) | 11 (64.71) | 18 (39.13) | |
| • Low disease activity b , n (%) | 8 (12.70) | 1 (5.88) | 7 (15.22) | |
| • Moderate disease activity c , n (%) | 24 (38.10) | 5 (29.41) | 19 (41.30) | |
| • High disease activity d , n (%) | 2 (3.17) | 0 | 2 (4.35) | |
| CDAI (mean ± SD) | 11.3 ± 8.7 | 7.6 ± 6.6 | 12.6 ± 9.0 | 0.026 |
| SDAI (mean ± SD) | 11.8 ± 8.8 | 8.0 ± 6.6 | 13.2 ± 9.2 | 0.026 |
| RAPID3 (mean ± SD) | 9.2 ± 5.7 | 8.8 ± 6.9 | 9.3 ± 5.2 | 0.448 |
| HAQ (mean ± SD) | 0.94 ± 0.71 | 0.82 ± 0.81 | 0.99 ± 0.67 | 0.277 |
CDAI, Clinical Disease Activity Index; DAS28, Disease Activity Score; HAQ, Health Assessment Questionnaire; hs-CRP, high-sensitivity C-reactive protein; PGA, patient global assessment, PhGA, global assessment; Rapid3, Routine Assessment of Patient Index Data 3; SD, standard deviation; SDAI, simplified Disease Activity Index; 28 SJC, 28 swollen joint counts; 28 TJC tender joint count; US synovitis, ultrasound synovitis; VAS pain, Visual Analogue Scale.
Remission: DAS28 ⩽ 2.6.
Low disease activity: 2.6–3.2.
Moderate disease activity: DAS28 3.2–5.1.
High disease activity: DAS28 ⩾ 5.1.
Calprotectin and APR as biomarkers of US synovitis
Mean plasma calprotectin levels were significantly higher in patients with US synovitis than in those without (0.89 ± 0.85 vs 0.30 ± 0.12 μg/ml; p = 0.0003), as occurred with hs-CRP serum levels (0.05 ± 0.08 vs 0.27 ± 0.41 mg/dL; p = 0.007) but not with ESR (16.9 ± 25.6 vs 7.8 ± 4.2 p = 0.474; Table 1 and Figure 1).
Figure 1.
Blood biomarkers classifying patients according to ultrasound synovitis [ultrasound synovitis in ⩾1 joint (SH ⩾ 2 + PD ⩾ 1)]: (a) hs-CRP levels according to ultrasound synovitis, (b) ESR levels according to ultrasound synovitis, and (c) plasma calprotectin levels according to ultrasound synovitis. The central line (orange) represents the median. The lateral lines the 25th (red) and 75th (green) percentiles.
Analysis of the correlation between blood biomarkers and US scores showed a moderate correlation between calprotectin and the three US scores (HS score Rho = 0.479; PD score Rho = 0.492; and global score Rho = 0.495). The association of calprotectin with these three US parameters was found in patients treated with anti-rIL-6 and JAKi, although the magnitude of the association was greater in patients treated with JAKi (Table 2).
Table 2.
Correlation between ultrasound synovitis scores and blood biomarkers.
| SH score (Rho; p value) | PD score (Rho; p value) | Global score (Rho; p value) | |
|---|---|---|---|
| Plasma calprotectin | 0.479 (p = 0.0001) | 0.492 (p < 0.0001) | 0.495 (p < 0.0001) |
| Plasma calprotectin in IL-6 inhibitor group | 0.391 (p = 0.010) | 0.349 (p = 0.023) | 0.383 (p = 0.012) |
| Plasma calprotectin in JAKi group | 0.630 (p = 0.002) | 0.703 (p = 0.0004) | 0.700 (p = 0.0004) |
| hs-CRP | 0.300 (p = 0.017) | 0.280 (p = 0.026) | 0.301 (p = 0.016) |
| hs-CRP in IL-6 inhibitor group | 0.166 (p = 0.294) | 0.085 (p = 0.594) | 0.147 (p = 0.352) |
| hs-CRP in JAKi group | 0.401 (p = 0.071) | 0.544 (p = 0.011) | 0.533 (p = 0.013) |
| ESR | 0.220 (p = 0.083) | 0.105 (p = 0.412) | 0.176 (p = 0.168) |
| ESR in IL-6 inhibitor group | 0.049 (p = 0.757) | –0.068 (p = 0.668) | 0.020 (p = 0.895) |
| ESR in JAKi group | 0.711 (p = 0.0003) | 0.659 (p = 0.0012) | 0.692 (p = 0.0005) |
hs-CRP, high-sensitivity C-reactive protein; IL, interleukin; JAKi, Janus kinase inhibitor; PD, power Doppler; SH, synovial hypertrophy.
hs-CRP serum levels also showed a correlation with the three US scores, although with a low positive correlation (Rho < 0.40). However, analysis of the correlation according to treatment showed that the correlation disappeared in patients receiving anti-rIL-6 (Table 2). ESR showed a good correlation with US scores in patients receiving JAKi but not in those treated with anti-rIL-6 (Table 2).
Plasma calprotectin had a very good discriminatory capacity, with an AUC of 0.795 [95% confidence interval (CI): 0.687–0.904]. The best cut-off was ⩾0.38, with a sensitivity of 67.4% and a specificity of 88.2%, which correctly classified 73% of patients with US synovitis. The positive likelihood ratio was 5.7. The discriminatory capacity of hs-CRP and ESR was lower, with an AUC of 0.721 and 0.564, respectively (Figure 2). The ability of plasma calprotectin to discriminate US synovitis was higher in patients treated with JAKi (AUC = 0.931, 95% CI: 0.820–1.000) than in those receiving anti-rIL-6 (AUC = 0.712; 95% CI: 0.558–0.867; Figure 2). hs-CRP and ESR had a good discriminatory capacity to detect US synovitis in patients treated with JAKi but not in those receiving anti-rIL-6 (Figure 3).
Figure 2.
ROC curves of blood biomarkers for ultrasound synovitis.
hs-CRP, high-sensitivity C-reactive protein.
Figure 3.
ROC curves of calprotectin, hs-CRP And ESR vs ultrasound synovitis according to type of treatment.
hs-CRP, high-sensitivity C-reactive protein.
When analysing the correlation between CDAI index and US score, we have found a lower correlation than that observed with calprotectin (correlation between CDAI and US scores: CDAI and HS score Rho = 0.298; CDAI and PD score Rho = 0.354; CDAI and global score Rho = 0.334, p value < 0.05).
Discussion
We evaluated the accuracy of plasma calprotectin in detecting US synovitis in patients with RA treated with anti-rIL-6 or JAKi. Our results show that plasma calprotectin levels are associated with US synovitis in these patients. Calprotectin demonstrated a higher capacity than traditional biomarkers, such as CRP or ESR, in detecting US synovitis in RA patients treated with anti-rIL-6 and a better correlation with US scores in patients receiving JAKi. Therefore, plasma calprotectin may be considered a sensitive biomarker of synovial inflammation in RA patients treated with anti-rIL-6 or JAKi.
The role of APR in the evaluation of disease activity in RA has been questioned in patients receiving anti-rIL-6, such as tocilizumab and sarilumab, both of which have an important effect on APR due to the reduction in hepatic synthesis of acute phase proteins due to the inhibition of IL6 stimuli.6,25 As demonstrated with tocilizumab, CRP serum levels decrease dramatically independently of the improvement in inflammatory activity, while there are detectable drug levels in the blood. 26 Therefore, CRP serum levels should not be used as a biomarker of inflammation in patients treated with anti-rIL-6 and the composite indices including APR, such as DAS28, should be avoided. Furthermore, significant residual synovial inflammation, even in patients in clinical remission using lower cut-off values than previously validated, has been demonstrated in patients receiving tocilizumab. 27
Calprotectin may be a sensitive biomarker of synovitis in RA patients treated with anti-rIL-6, due to the high levels observed in the blood, which reflect local synovial inflammation rather than a systemic effect as occurs with APR. 28 Recent studies have shown that calprotectin is increased in the serum or plasma of patients with RA and other immunodetected diseases, reflecting a relevant role of neutrophilic activation in these diseases. 29 Calprotectin correlates better with active inflammatory active disease in RA than traditional APR such as CRP and ESR. 30
To our knowledge, this is the first study to evaluate the performance of blood calprotectin in RA patients treated with JAKi, a family of targeted therapies that also have also an important impact on APR. 3 Our results show that, in patients treated with JAKi, plasma calprotectin has a higher correlation with US synovitis than hs-CRP. Also, this correlation is higher than those observed with a clinical activity index such as CDAI. The discriminatory capacity of calprotectin in detecting US synovitis was also very high, but similar to that observed with hs-CRP. By contrast, hs-CRP and ESR did not show the same relevance in patients treated with anti-rIL-6, where only calprotectin was a biomarker of US synovitis.
US is a sensitive imaging technique for the detection of active synovitis in patients with RA and other immune-mediated rheumatic conditions. Our results confirm the association of calprotectin with US synovitis in RA as documented in other studies.15,16,31,32 We have previously demonstrated that, in patients receiving tumour necrosis factor inhibitor (TNFi), calprotectin is a good biomarker of US synovitis, even in patients in remission or with low disease activity. 16 We have replicated these findings for the first time in RA patients treated with anti-rIL-6 and JAKi, most of whom were in remission or with low disease activity.
Our study has some limitations. We included a relatively small sample size, especially of patients treated with JAKi. On the contrary, patients were predominantly in remission or with low disease activity. However, even in this context, calprotectin showed a good discriminatory capacity for US synovitis. No attempt was made to further distinguish the different antirheumatic drugs, to avoid very small samples that would make data interpretation difficult. However, we cannot say whether differences might be observed within the same therapeutic group.
In conclusion, plasma calprotectin is a good biomarker of US synovitis in patients with RA treated with anti-rIl-6, whereas traditional APR (CRP or ESR) do not reflect local synovial inflammation detected by US. Some differences emerged in RA patients treated with JAKi, where calprotectin is also a good biomarker of US synovitis in RA but in whom APR also reflect synovial inflammation. We suggest that plasma calprotectin is a valuable biomarker of synovitis in these patients.
Supplemental Material
Supplemental material, sj-docx-1-tab-10.1177_1759720X221114105 for Plasma calprotectin as a biomarker of ultrasound synovitis in rheumatoid arthritis patients receiving IL-6 antagonists or JAK inhibitors by Beatriz Frade-Sosa, Andrés Ponce, José Inciarte-Mundo, Rosa Morlà, Viginia Ruiz-Esquide, Laura Macías, Ana Belen Azuaga, Julio Ramirez, Juan D. Cañete, Jordi Yague, Josep M. Auge, José A. Gomez-Puerta and Raimon Sanmarti in Therapeutic Advances in Musculoskeletal Disease
Acknowledgments
The authors acknowledge the assistance provided by rheumatology unit nurses (Nuria Sapena and Marta Bassas) statistical help from M Jesus Garcia Yebenes (Inmusc) and technical advice from David Buss.
Footnotes
ORCID iDs: Beatriz Frade-Sosa 
https://orcid.org/0000-0002-5867-8434
Andrés Ponce
https://orcid.org/0000-0003-3068-5752
Viginia Ruiz-Esquide
https://orcid.org/0000-0002-2657-6601
José A. Gomez-Puerta
https://orcid.org/0000-0001-8177-702X
Raimon Sanmarti
https://orcid.org/0000-0002-8864-3806
Supplemental material for this article is available online.
Contributor Information
Beatriz Frade-Sosa, Department of Rheumatology, Hospital Clinic of Barcelona, Barcelona, Spain.
Andrés Ponce, Department of Rheumatology, Hospital Clinic of Barcelona, Barcelona, Spain.
José Inciarte-Mundo, Fundació Clínic per a la Recerca Biomédica, Barcelona, Spain.
Rosa Morlà, Department of Rheumatology, Hospital Clinic of Barcelona, Barcelona, Spain.
Viginia Ruiz-Esquide, Department of Rheumatology, Hospital Clinic of Barcelona, Barcelona, Spain.
Laura Macías, Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Barcelona, Spain.
Ana Belen Azuaga, Department of Rheumatology, Hospital Clinic of Barcelona, Barcelona, Spain.
Julio Ramirez, Department of Rheumatology, Hospital Clinic of Barcelona, Barcelona, Spain.
Juan D. Cañete, Department of Rheumatology, Hospital Clinic of Barcelona, Barcelona, Spain
Jordi Yague, Department of Immunology, Hospital Clinic – CDB, Barcelona, Spain.
Josep M. Auge, Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Barcelona, Spain
José A. Gomez-Puerta, Department of Rheumatology, Hospital Clinic of Barcelona, Barcelona, Spain
Raimon Sanmarti, Department of Rheumatology, Hospital Clinic of Barcelona, Carrer Villarroel 170, Barcelona 08170, Spain.
Declarations
Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki and was approved by the Clinical Research Ethics Committee of the Hospital Clinic of Barcelona. Informed consent was obtained from all patients before study enrolment
Consent for publication: Not applicable.
Author contributions: Beatriz Frade-Sosa: Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Writing – original draft; Writing – review & editing.
Andrés Ponce: Data curation; Investigation; Methodology; Project administration; Writing – original draft; Writing – review & editing
Jose Inciarte-Mundo: Investigation; Writing – review & editing.
Rosa Morlà: Writing – review & editing.
Viginia Ruiz-Esquide: Conceptualization; Writing – review & editing.
Laura Macías: Conceptualization; Investigation.
Ana Belen Azuaga: Investigation; Writing – review & editing.
Julio Ramirez: Writing – review & editing.
Juan D. Cañete: Conceptualization; Writing – review & editing.
Jordi Yague: Investigation; Writing – review & editing.
Josep M. Auge: Conceptualization; Investigation; Writing – review & editing.
Jose A. Gomez-Puerta: Investigation; Methodology; Writing – review & editing.
Raimon Sanmarti: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Supervision; Validation; Visualization; Writing – original draft; Writing – review & editing.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
Competing interests: BFS received support for attending meetings from Pfizer, AbbVie, Lilly, and GSK. JIM received fees from Pfizer, AbbVie, Roche, UCB, Lilly, BMS, and MSD for research grant, consultation, and/or speaker; and is an AbbVie employee. LM received support for attending meetings and/or travel from Diasorin in 19 October (LabClin Congress). JAGP received speaker honoraria from AbbVie, BMS, Galápagos, GSK, Lilly, Pfizer, Sanofi, and Roche. RS received speaker honoraria and/or investigation grants from AbbVie, BMS, Gebro-Pharma, Lilly, MSD, Pfizer, Sanofi, and Roche. The remaining authors declare they have no conflicts of interest. No pharmaceutical companies have participated or influenced the development of this manuscript
Availability of data and materials: Not applicable.
References
- 1. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020; 79: 685–699. [DOI] [PubMed] [Google Scholar]
- 2. Navarro G, Taroumian S, Barroso N, et al. Tocilizumab in rheumatoid arthritis: a meta-analysis of efficacy and selected clinical conundrums. Semin Arthritis Rheum 2014; 43: 458–469. [DOI] [PubMed] [Google Scholar]
- 3. Taylor PC. Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis. Rheumatology (Oxford) 2019; 58(Suppl. 1): i17–i26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Naka T, Nishimoto N, Kishimoto T. The paradigm of IL-6: from basic science to medicine. Arthritis Res 2002; 4(Suppl. 3): S233–S242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Asai S, Takahashi N, Kobayakawa T, et al. Comparison of the effects of baricitinib and tocilizumab on disease activity in patients with rheumatoid arthritis: a propensity score matching analysis. Clin Rheumatol 2021; 40: 3143–3151. [DOI] [PubMed] [Google Scholar]
- 6. Smolen JS, Aletaha D. Interleukin-6 receptor inhibition with tocilizumab and attainment of disease remission in rheumatoid arthritis: the role of acute-phase reactants. Arthritis Rheum 2011; 63: 43–52. [DOI] [PubMed] [Google Scholar]
- 7. Austermann J, Spiekermann C, Roth J. S100 proteins in rheumatic diseases. Nat Rev Rheumatol 2018; 14: 528–541. [DOI] [PubMed] [Google Scholar]
- 8. Youssef P, Roth J, Frosch M, et al. Expression of myeloid related proteins (MRP) 8 and 14 and the MRP8/14 heterodimer in rheumatoid arthritis synovial membrane. J Rheumatol 1999; 26: 2523–2528. [PubMed] [Google Scholar]
- 9. Hammer HB, Odegard S, Fagerhol MK, et al. Calprotectin (a major leucocyte protein) is strongly and independently correlated with joint inflammation and damage in rheumatoid arthritis. Ann Rheum Dis 2007; 66: 1093–1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Hammer HB, Ødegård S, Syversen SW, et al. Calprotectin (a major S100 leucocyte protein) predicts 10-year radiographic progression in patients with rheumatoid arthritis. Ann Rheum Dis 2010; 69: 150–154. [DOI] [PubMed] [Google Scholar]
- 11. Choi IY, Gerlag DM, Herenius MJ, et al. MRP8/14 serum levels as a strong predictor of response to biological treatments in patients with rheumatoid arthritis. Ann Rheum Dis 2015; 74: 499–505. [DOI] [PubMed] [Google Scholar]
- 12. Inciarte-Mundo J, Ramirez J, Hernández MV, et al. Calprotectin strongly and independently predicts relapse in rheumatoid arthritis and polyarticular psoriatic arthritis patients treated with tumor necrosis factor inhibitors: a1-year prospective cohort study. Arthritis Res Ther 2018; 20: 275. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Joshua F, Edmonds J, Lassere M. Power Doppler ultrasound in musculoskeletal disease: a systematic review. Semin Arthritis Rheum 2006; 36: 99–108. [DOI] [PubMed] [Google Scholar]
- 14. Brown AK, Quinn MA, Karim Z, et al. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum 2006; 54: 3761–3773. [DOI] [PubMed] [Google Scholar]
- 15. Hammer H, Fagerhol MK, Wien T, et al. The soluble biomarker calprotectin (a S100 protein) is associated to ultrasonographic synovitis scores and is sensitive to change in patients with rheumatoid arthritis treated with adalimumab. Arthritis Res Ther 2011; 13: R178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Inciarte-Mundo J, Ramirez J, Hernández MV, et al. Calprotectin and TNF trough serum levels identify power Doppler ultrasound synovitis in rheumatoid arthritis and psoriatic arthritis patients in remission or with low disease activity. Arthritis Res Ther 2016; 18: 160. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Inciarte-Mundo J, Ruiz-Esquide V, Hernández MV, et al. Calprotectin more accurately discriminates the disease status of rheumatoid arthritis patients receiving tocilizumab than acute phase reactants. Rheumatology (Oxford) 2015; 54: 2239–2243. [DOI] [PubMed] [Google Scholar]
- 18. Jarlborg M, Courvoisier DS, Lamacchia C, et al. Serum calprotectin: a promising biomarker in rheumatoid arthritis and axial spondyloarthritis. Arthritis Res Ther 2020; 622: 105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010; 69: 1580–1588. [DOI] [PubMed] [Google Scholar]
- 20. Backhaus M, Burmester GR, Gerber T, et al. Guidelines for musculoskeletal ultrasound in rheumatology. Ann Rheum Dis 2001; 60: 641–649. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Wakefield RJ, Balint PV, Szkudlarek M, et al. Musculoskeletal ultrasound including definitions for ultrasonographic pathology. J Rheumatol 2005; 32: 2485–2487. [PubMed] [Google Scholar]
- 22. Szkudlarek M, Court-Payen M, Jacobsen S, et al. Interobserver agreement in ultrasonography of the finger and toe joints in rheumatoid arthritis. Arthritis Rheum 2003; 48: 955–962. [DOI] [PubMed] [Google Scholar]
- 23. Ramírez J, Ruíz-Esquide V, Pomés I, et al. Patients with rheumatoid arthritis in clinical remission and ultrasound-defined active synovitis exhibit higher disease activity and increased serum levels of angiogenic biomarkers. Arthritis Res Ther 2014; 16: 1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med 2007; 147: 573–577. Erratum in: Ann Intern Med 2008; 148: 168. [DOI] [PubMed] [Google Scholar]
- 25. Burmester GR, Bykerk VP, Buch MH, et al. Sarilumab monotherapy versus sarilumab and methotrexate combination therapy in patients with rheumatoid arthritis. Rheumatology (Oxford) 2021; 11: keab676. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Nishimoto N, Yoshizaki K, Maeda K, et al. Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study. J Rheumatol 2003; 30: 1426–1435. [PubMed] [Google Scholar]
- 27. Schoels M, Alasti F, Smolen JS, et al. Evaluation of newly proposed remission cut-points for Disease Activity Score in 28 joints (DAS28) in rheumatoid arthritis patients upon IL-6 pathway inhibition. Arthritis Res Ther 2017; 19: 155. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Donato R, Cannon BR, Sorci G, et al. Functions of S100 proteins. Curr Mol Med 2013; 13: 24–57. [PMC free article] [PubMed] [Google Scholar]
- 29. Romand X, Bernardy C, Nguyen MVC, et al. Systemic calprotectin and chronic inflammatory rheumatic diseases. Joint Bone Spine 2019; 86: 691–698. [DOI] [PubMed] [Google Scholar]
- 30. Inciarte-Mundo J, Hernández MV, Ruiz-Esquide V, et al. Serum calprotectin versus acute-phase reactants in the discrimination of inflammatory disease activity in rheumatoid arthritis patients receiving tumor necrosis factor inhibitors. Arthritis Care Res 2016; 68: 899–906. [DOI] [PubMed] [Google Scholar]
- 31. Nordal HH, Brokstad KA, Solheim M, et al. Calprotectin (S100A8/A9) has the strongest association with ultrasound-detected synovitis and predicts response to biologic treatment: results from a longitudinal study of patients with established rheumatoid arthritis. Arthritis Res Ther 2017; 19: 3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Hurnakova J, Zavada J, Hanova P, et al. Serum calprotectin (S100A8/9): an independent predictor of ultrasound synovitis in patients with rheumatoid arthritis. Arthritis Res Ther 2015; 17: 252. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Supplementary Materials
Supplemental material, sj-docx-1-tab-10.1177_1759720X221114105 for Plasma calprotectin as a biomarker of ultrasound synovitis in rheumatoid arthritis patients receiving IL-6 antagonists or JAK inhibitors by Beatriz Frade-Sosa, Andrés Ponce, José Inciarte-Mundo, Rosa Morlà, Viginia Ruiz-Esquide, Laura Macías, Ana Belen Azuaga, Julio Ramirez, Juan D. Cañete, Jordi Yague, Josep M. Auge, José A. Gomez-Puerta and Raimon Sanmarti in Therapeutic Advances in Musculoskeletal Disease