Calprotectin – clinical and diagnostic value in rheumatoid arthritis

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation leading to joint damage and functional impairment. Accurate biomarkers are critical in RA for diagnosing the disease, assessing inflammation, monitoring treatment response, and predicting outcomes. Traditionally, acute-phase reactants such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are used to gauge disease activity. However, these markers have important limitations, a substantial subset of RA patients can have active disease with normal CRP/ESR levels [1]. In fact, low CRP and ESR are observed in up to ~40% of RA patients despite evident synovitis [2]. Moreover, certain therapies (e.g. IL-6 inhibitors like tocilizumab) directly suppress CRP production, making CRP unreliable in those contexts [3]. This has prompted interest in alternative inflammatory biomarkers that might better reflect RA disease activity. One promising candidate is calprotectin, a protein released by activated myeloid cells. Recent literature suggests that calprotectin may provide additional clinical and diagnostic value in RA beyond conventional markers [4, 5]. This review provides a comprehensive overview of calprotectin’s role in adult RA, comparing it to CRP/ESR, examining how and where it is measured, and evaluating its utility in disease monitoring and prognostication based on the latest high-impact studies.

The aim of this review is to critically appraise the current evidence on calprotectin as a biomarker in adult rheumatoid arthritis, focusing on its diagnostic and monitoring value compared with CRP and ESR, its measurement in serum, synovial fluid and feces, and its utility in assessing disease activity, therapeutic response, and prognosis.

Material and methods

Study design. This manuscript is a systematic narrative review of the literature addressing the clinical, diagnostic, and monitoring value of calprotectin (S100A8/A9) in adult patients with rheumatoid arthritis (RA). The review was conducted in accordance with established principles for evidence synthesis in biomedical research and aimed to ensure methodological transparency and reproducibility.

Data sources and search strategy. A comprehensive literature search was performed in the following electronic databases: MEDLINE (via PubMed) and Embase (via Ovid). The search primarily focused on studies published between January 2010 and August 2025, reflecting the period during which calprotectin became a clinically relevant biomarker in rheumatology. However, some studies published before 2010 were also included to provide historical context or foundational data, and were cited where they contributed to the overall analysis. Thus, the main analysis focuses on studies from 2010–2025 without disregarding relevant information from earlier works.

The search strategies combined controlled vocabulary (MeSH/Emtree terms) and free-text keywords. The core search terms included: “rheumatoid arthritis”, “calprotectin” OR “S100A8/A9” OR “MRP8/14”. These were combined using Boolean operators with the following terms: “biomarker”, “disease activity”, “C-reactive protein”, “erythrocyte sedimentation rate”, “synovial fluid”, “fecal calprotectin”, “ultrasound”, “treatment response”, “radiographic progression”. An example PubMed search string was: (“rheumatoid arthritis” [MeSH] OR “rheumatoid arthritis”) AND (“calprotectin” OR “S100A8/A9” OR “MRP8/14”). Reference lists of key review articles and high-impact original studies were manually screened to identify additional relevant publications not captured by the electronic search.

Eligibility criteria. Studies were selected based on the following inclusion criteria: original research articles, systematic reviews, or meta-analyses; adult patients (≥18 years) diagnosed with rheumatoid arthritis; measurement of calprotectin in serum, plasma, synovial fluid, or feces; evaluation of associations with disease activity, imaging findings, therapeutic response, prognosis, or relapse; articles published in English.

Exclusion criteria were: pediatric populations (e.g., juvenile idiopathic arthritis); animal or in vitro studies; case reports or small case series (<10 patients); studies not specifically analyzing calprotectin (e.g., calprotectin mentioned only as part of multiplex panels without independent analysis); non-RA inflammatory diseases unless RA-specific data were separately reported.

Study selection process. Two reviewers independently screened titles and abstracts for relevance. Full-text articles were retrieved for studies meeting inclusion criteria or when eligibility was unclear. Discrepancies were resolved by consensus discussion.

Data extraction. From each included study, the following data were systematically extracted: study design and population characteristics; sample size and disease duration; biological matrix used for calprotectin measurement (serum, plasma, synovial fluid, feces); laboratory assay type (ELISA, turbidimetric immunoassay, chemiluminescent assay); reported calprotectin values and cut-off thresholds; correlations with clinical disease activity indices (DAS28, CDAI, SDAI), imaging findings (ultrasound, radiography), and laboratory markers (CRP, ESR); associations with treatment response, remission, relapse, or radiographic progression. Data were extracted qualitatively and quantitatively where applicable.

Assessment of methodological quality. The methodological quality of included studies was evaluated descriptively, focusing on: adequacy of patient selection; clear definition of RA diagnosis and disease activity measures; standardization and reproducibility of calprotectin assays; appropriate statistical analyses; adjustment for relevant confounders (e.g., treatment type, disease duration). Given the narrative nature of the review and heterogeneity of study designs, no formal risk-of-bias scoring tool was applied.

Data synthesis. Due to substantial heterogeneity across studies regarding populations, assay methodologies, outcome measures, and follow-up duration, a qualitative narrative synthesis was performed rather than a quantitative meta-analysis. Results were grouped thematically into: biological rationale of calprotectin in RA; measurement methodologies and analytical considerations; comparison with traditional acute-phase reactants (CRP, ESR); association with clinical and imaging disease activity; prognostic value and role in therapeutic monitoring. This structured synthesis allows for reproducibility of the review process and facilitates comparison across studies.

Results

Calprotectin, also known as the S100A8/A9 complex or myeloid-related protein 8/14 (MRP8/14), is a calcium-binding heterodimer abundant in neutrophils and monocytes. It functions as a damage-associated molecular pattern (DAMP) protein or “alarmin” that amplifies innate immune responses [5]. When released extracellularly during inflammation, calprotectin can trigger chemotaxis and leukocyte recruitment (via Toll-like receptor 4 activation), and it promotes neutrophil and macrophage activation in inflamed tissues [6]. In RA, the synovial milieu is rich in neutrophils, especially in the inflamed joint fluid and at the cartilage–pannus junction, making calprotectin highly relevant to local pathology. The synovial tissue of RA patients shows markedly elevated calprotectin levels in areas of active inflammation, reflecting local production by infiltrating leukocytes [7]. Calprotectin is also detectable systemically in the blood; indeed, RA patients have higher calprotectin concentrations in serum and plasma compared to healthy individuals. Serum calprotectin levels in healthy people range roughly from 0.1 to 1.6 μg/mL [5]. Notably, one study proposed that a serum calprotectin cut-off above ~0.9 μg/mL could help distinguish inflammatory arthritis (such as RA) from non-inflammatory joint conditions, highlighting potential diagnostic value [8]. Overall, calprotectin’s origin from innate immune cells and its abundance at sites of inflammation provide a strong biological rationale for its use as an RA biomarker.

Measurement of calprotectin: serum, synovial fluid, and feces. Serum/plasma calprotectin: Clinically, calprotectin is most often measured in serum or plasma. The assays include enzyme-linked immunosorbent assays (ELISA) and newer automated immunoassays. For example, a particle-enhanced turbidimetric immunoassay (PETIA) for calprotectin in plasma/serum has been developed to enable rapid, high-throughput testing [9]. Studies have shown that results from different platforms (e.g. ELISA vs. chemiluminescent immunoassay) are strongly correlated, and assay standardization efforts are underway [10]. Serum calprotectin levels tend to be significantly elevated in RA patients relative to healthy controls, and they vary widely with disease activity [3]. It is important to note that absolute values can differ by assay and sample handling (serum vs. plasma), so consistency in methodology is key when comparing studies.

Synovial fluid calprotectin: Given that calprotectin is released at sites of inflammation, it is unsurprising that synovial fluid (SF) from RA joints contains very high calprotectin levels. In fact, RA SF calprotectin concentrations often exceed corresponding blood levels, indicating substantial local production in inflamed joints [10]. This makes SF calprotectin a compelling marker of local joint inflammation. The 2015 systematic review by Abildtrup et al. concluded that RA synovial fluid has markedly elevated calprotectin, supporting the concept of calprotectin as a synovial biomarker [1]. SF calprotectin is measured using the same immunoassays applied to serum or plasma samples. Although sampling synovial fluid is invasive and not routine for all patients, research studies have leveraged SF calprotectin levels to better understand joint-specific disease activity. Elevated SF calprotectin correlates with higher local leukocyte counts and erosive changes in RA joints [10], reinforcing its link to aggressive synovitis.

Fecal calprotectin: Calprotectin is widely known as a fecal biomarker for intestinal inflammation (e.g. in inflammatory bowel disease). In RA, fecal calprotectin is not a standard assessment, since RA primarily affects joints. However, some studies have explored fecal calprotectin in RA patients to investigate possible subclinical gut inflammation or coexisting conditions. These investigations are based on the hypothesis of a “mucosal origin” of RA autoimmunity or the high use of NSAIDs (which can inflame the gut). Small studies have noted that RA patients, on average, do not have significantly elevated fecal calprotectin unless gastrointestinal (GI) symptoms or concurrent GI disease is present [11]. By contrast, fecal calprotectin is much more relevant in spondyloarthritis, where it correlates with disease activity due to frequent gut involvement [12]. Therefore, while fecal calprotectin can be measured in RA research settings, it is generally not useful for routine RA management and is not a focus in current RA literature. The primary focus remains on blood (and occasionally synovial fluid) calprotectin for assessing RA inflammation.

Calprotectin vs traditional biomarkers (CRP and ESR). A central question is how calprotectin compares to conventional inflammatory markers in RA. Multiple studies indicate that calprotectin correlates better with RA disease activity than CRP or ESR in many situations [13]. Several points of comparison emerge from recent literature:

§ Sensitivity to active disease: Calprotectin appears more sensitive in detecting active joint inflammation than CRP/ESR. For instance, even when CRP and ESR are within normal ranges, calprotectin can be elevated in patients with clinically active RA. One study found that in patients considered in remission by clinical exam, calprotectin levels were significantly lower in those with truly no swollen joints versus those with subclinical swelling, whereas CRP/ESR did not differentiate these groups [14]. This suggests calprotectin can unmask residual inflammation that CRP misses. Indeed, calprotectin was able to distinguish patients with ≥1 swollen joint from those with none, even in cases where CRP and ESR were normal [14]. By contrast, CRP and ESR often remain low in a substantial fraction of patients despite active synovitis [15].

§ Effect of therapies (IL-6 inhibition): CRP is an IL-6-dependent acute phase reactant, so IL-6 blocking therapies (tocilizumab) can artificially suppress CRP levels. Calprotectin, being released by immune cells, is not directly suppressed by IL-6 blockade [13]. A study of RA patients on tocilizumab showed that calprotectin more accurately reflected disease activity than CRP – in fact, calprotectin was independent of tocilizumab drug levels, whereas CRP was rendered unreliable [16]. Inciarte-Mundo et al. reported that calprotectin discriminated active vs. inactive disease in IL-6 inhibitor–treated patients far better than acute-phase reactants [17]. Thus, calprotectin can be particularly useful when CRP is artificially lowered by therapy[10].

§ Correlation strength: Quantitatively, a 2015 meta-analysis (31 studies) found serum calprotectin had a moderate-to-strong positive correlation with CRP (pooled correlation coefficient ~0.58) and with disease activity scores (DAS28 correlation ~0.48) [18].While calprotectin correlates with CRP (since both rise in inflammation), many studies have noted that calprotectin tracks more closely with clinical disease measures (swollen joint counts, patient/global scores) than CRP or ESR do [19]. For example, calprotectin correlates strongly with composite disease indices and global inflammation scores, even outperforming CRP/ESR in reflecting patient-global assessments and ultrasound synovitis [20]. This is especially evident in seropositive RA: one analysis showed calprotectin’s correlation with disease was much stronger in ACPA positive RA patients, implying it may be a particularly good marker in the more severe, seropositive subset [21].

§ Ultrasound and subclinical inflammation: Modern imaging like musculoskeletal ultrasound (MSUS) can detect subclinical synovitis via power Doppler signals. Calprotectin has shown the highest correlation with ultrasound Power Doppler scores compared to other lab markers [22]. Even in patients in clinical remission or low disease activity, elevated calprotectin and detectable ultrasound synovitis often go hand-in-hand. Inciarte-Mundo et al. demonstrated that a combination of serum calprotectin and ultrasound power Doppler findings could identify ongoing synovial inflammation in RA and psoriatic arthritis patients who were otherwise in remission by clinical criteria [16]. This underscores calprotectin’s role in capturing inflammatory activity that traditional measures might overlook.

In summary, calprotectin offers some clear advantages over CRP and ESR as an inflammation biomarker in RA. It is more sensitive to ongoing joint inflammation (fewer false negatives for active disease), remains reliable even when certain therapies confound CRP levels, and aligns closely with both clinical and imaging indicators of synovitis. These strengths make a case for incorporating calprotectin into RA disease activity assessments alongside or in place of conventional acute-phase reactants.

Calprotectin and disease activity in RA. Numerous studies have established that calprotectin levels reflect RA disease activity and burden of inflammation. Higher calprotectin is associated with more active and severe RA on multiple measures:

§ Clinical disease activity scores: RA patients with high disease activity (by DAS28, CDAI, SDAI, etc.) tend to have significantly elevated serum calprotectin compared to those in low disease activity or remission [19]. In a large cohort study of 969 RA patients (Jarlborg et al., 2020), calprotectin levels stratified patients by disease activity: those in the top quartile of calprotectin had markedly higher swollen joint counts and DAS28 scores than those in the lowest quartile [20]. In fact, all clinical outcomes (swollen/tender joint counts, global scores, HAQ disability index) worsened across increasing calprotectin quartiles. This indicates a robust association between serum calprotectin and clinical RA activity. Additionally, calprotectin levels tend to be particularly high in patients with seropositive RA and those with more aggressive disease courses [17].

§ Imaging and joint damage: Elevated calprotectin not only correlates with active inflammation but also with structural damage over time. Studies have found that baseline calprotectin can predict radiographic progression of joint damage. For example, Hammer et al. (2010) observed that serum calprotectin was independently associated with erosive joint damage, even when controlling for CRP, RF, DAS28, and other factors [5]. In that longitudinal cohort, patients with normal baseline calprotectin had significantly less radiographic damage after 10 years than those with high calprotectin. Similarly, a systematic review reported that high baseline MRP8/14 levels were a significant independent predictor of future erosive progression in RA [23]. This prognostic link likely reflects that calprotectin mirrors the underlying inflammatory processes driving joint destruction. In addition to x-ray damage, calprotectin correlates with ultrasound-detected synovitis scores, as noted earlier, reinforcing its relationship with the extent of articular inflammation.

§ Disease severity and function: High calprotectin has been linked to worse patient-reported outcomes and functional status. The Jarlborg et al. study found that patients in the highest calprotectin quartile had higher Health Assessment Questionnaire (HAQ) disability scores, indicating more functional impairment [20]. Moreover, calprotectin tends to be elevated in those with extra-articular manifestations or higher global assessments of disease activity [24]. All these connections paint a consistent picture: calprotectin is a strong marker of both the inflammatory activity and the clinical severity of RA.

One caveat is that calprotectin levels can be quite variable between individuals (significant inter-patient and intra-patient variability) [25]. Factors like age, comorbidities (infections, other inflammatory conditions), and assay differences can influence absolute values. Thus, while trends and correlations are clear at the group level, using absolute calprotectin cut-offs for disease activity in individual patients may require personalized baselines or repeated measures. Nonetheless, the overall evidence strongly supports calprotectin as a valuable indicator of RA disease activity that aligns with both clinical and objective measures of inflammation.

Diagnostic and differential diagnostic value. The primary role of calprotectin in RA is as a disease activity marker, but researchers have also explored its utility in diagnosis and in differentiating RA from other conditions. RA diagnosis usually relies on clinical criteria and autoantibodies (RF, ACPA). Calprotectin is not a specific marker for RA, since it is elevated in any inflammatory state. However, its levels can still provide diagnostic clues in certain scenarios:

§ RA vs. healthy or non-inflammatory arthropathy: As noted, RA patients have higher serum calprotectin on average than healthy individuals [26]. Using calprotectin to distinguish truly inflammatory arthritis from non-inflammatory joint pain or osteoarthritis has shown some promise. One study proposed a serum calprotectin cut-off (~0.9 μg/mL) to differentiate RA or other inflammatory arthritis from non-inflammatory arthritis, with levels above that threshold indicating an inflammatory process [8]. Similarly, calprotectin is typically normal in osteoarthritis (OA) and other degenerative joint diseases, so an elevated calprotectin might favor an inflammatory rheumatic disease. De Seny et al. (2008) found that calprotectin measured by mass spectrometry or ELISA could help discriminate RA from OA, as RA patients had significantly higher levels [27]. That said, calprotectin alone is not diagnostic for RA specifically – it should be interpreted in context with clinical findings and other tests.

§ RA vs. other rheumatic diseases: Calprotectin is elevated in many rheumatic and autoimmune diseases (e.g. psoriatic arthritis, systemic lupus, ankylosing spondylitis). However, there may be quantitative differences. RA tends to feature very high calprotectin when joints are actively inflamed, often higher than in conditions with less neutrophil involvement. For instance, psoriatic arthritis (PsA) patients in some studies did not show as clear a correlation between calprotectin and disease activity as RA patients did [28]. This could imply different inflammatory profiles. In clinical practice, extreme calprotectin elevations might point toward a rheumatoid/inflammatory arthritis (RA, PsA, etc.) rather than a purely axial disease or non-inflammatory condition, but it would not distinguish between RA and another inflammatory arthritis on its own. An interesting point is that calprotectin has been recommended as a diagnostic aid in adult-onset Still’s disease and systemic JIA – diseases with fever and systemic inflammation, where extremely high calprotectin levels occur. In RA, the diagnostic focus remains on immunologic markers (RF/ACPA), but calprotectin can support the impression of “active inflammation” when the picture is unclear.

In summary, calprotectin’s diagnostic value in RA is auxiliary: it confirms the presence of inflammation and can help distinguish inflammatory arthritis from non-inflammatory causes of joint pain. It is not specific for RA, but a significantly elevated serum calprotectin in a patient with joint symptoms raises suspicion for an inflammatory rheumatic condition (like RA) rather than osteoarthritis. Conversely, a normal calprotectin might prompt looking for non-inflammatory causes if RA is uncertain. Ongoing research is examining calprotectin in “pre-clinical” RA or undifferentiated arthritis to see if it can predict progression to definite RA, but definitive evidence is still limited. Clinicians should use calprotectin in conjunction with established diagnostic criteria rather than as a standalone test for RA.

Therapeutic monitoring: calprotectin in treatment response and relapse. One of the most clinically relevant aspects of any biomarker is whether it can guide therapy decisions. For calprotectin, researchers have evaluated its role in monitoring treatment response to disease-modifying antirheumatic drugs (DMARDs) and biologics, and its ability to predict outcomes such as remission or relapse. Key findings include:

·  Decline with effective therapy: Calprotectin levels tend to fall as patients respond to treatment. In early RA patients starting therapy, studies observed that decreases in serum calprotectin correlated with improvements in swollen joint counts over time [29]. Andrés Cerezo et al. (2011) reported that as patients with new-onset RA were treated, those who improved clinically showed significant drops in S100A8/A9 levels, paralleling reduction in joint inflammation [3]. In another cohort, calprotectin was noted as the first biomarker to normalize in responders, even before CRP in some cases. Importantly, calprotectin reduction was associated with achieving remission: patients who attained remission had a significant reduction in calprotectin, whereas non-responders maintained higher levels [3]. These observations align with calprotectin being directly tied to synovitis – as inflammation resolves, neutrophil activation abates and calprotectin production drops accordingly.

·  Indicator of residual disease on biologics: As discussed, patients on IL-6 or TNF inhibitors often have low CRP despite possible residual synovitis. In such cases, calprotectin can serve as a sensitive monitor of ongoing inflammation. Studies on TNF inhibitor therapy showed that calprotectin is associated with ultrasound-detected synovitis even when patients are in low clinical disease activity [16]. For example, Hammer et al. (2011) demonstrated that in RA patients treated with adalimumab, serum calprotectin changes mirrored ultrasound improvements and were sensitive to change with therapy [11]. Thus, serial calprotectin measurements might be useful to track deeper remission status, complementing clinical exams.

·  Predicting treatment response: Whether baseline calprotectin can predict who will respond to a given therapy has been debated. Earlier studies suggested high baseline calprotectin might indicate a more inflammatory phenotype that could respond well to certain biologics. Indeed, one 2015 study in early RA drug trials found that MRP8/14 was a sensitive biomarker for effective treatment, changing early in responders [30]. However, the most recent and rigorous data indicate calprotectin adds little beyond CRP in predicting response to TNF inhibitors. A large post-hoc analysis of 470 RA patients (from two trials of adalimumab/etanercept) found that patients with higher baseline CRP were more likely to achieve a good EULAR 3-month response to TNF blockers, but baseline calprotectin did not independently predict response [20]. In fact, adding calprotectin to a model already containing CRP did not improve prediction of treatment outcome (p = 0.62). Furthermore, baseline calprotectin alone was not significantly associated with response by CDAI criteria (p = 0.839) [30]. These results suggest that for TNF inhibitors, measuring calprotectin before treatment may not be more informative than just measuring CRP. It appears that a high CRP (indicating active inflammation) is a good predictor of biologic response, and calprotectin, which usually parallels CRP, does not substantially change that equation in a predictive model [25]. Therefore, current evidence does not support using baseline calprotectin as a routine predictor of who will respond to therapy, especially if CRP is already considered.

·  Predicting relapse and flare: On the other hand, calprotectin may have value in predicting disease flare or relapse after a period of remission, which is a different clinical scenario. A notable study by Inciarte-Mundo et al. (2018) followed RA patients in remission or low disease activity who were on TNF inhibitors, and asked whether calprotectin could predict relapse. Strikingly, patients who later relapsed had significantly higher baseline calprotectin levels (while in remission) than those who maintained remission [17]. In this study, calprotectin was an extremely strong predictor of flare: ROC analysis showed an AUC of 1.0 for calprotectin, meaning it perfectly discriminated relapsers vs. non-relapsers (though the sample of relapses was small). Survival analysis demonstrated much shorter time-to-relapse in patients with high calprotectin, and in multivariate Cox regression, baseline calprotectin was the only independent predictor of relapse (HR ≈ 2.4, p = 0.002) [25]. These results, if replicated, suggest that measuring calprotectin in patients who appear clinically quiescent could identify those with smoldering subclinical disease at risk of imminent flare. In practical terms, a persistently high calprotectin in a patient in clinical remission might alert clinicians to not taper therapy or to monitor more closely, as a flare could be looming. It’s worth noting that this was a single-center study; larger studies would help confirm the predictive power for relapse. Nonetheless, it highlights a potential role for calprotectin in guiding maintenance therapy (e.g. decisions about tapering DMARDs or biologics).

·  Therapeutic targets and decisions: Could calprotectin be a treatment target, analogous to “treat-to-target” with CRP or DAS28? While not formally in guidelines, some experts have proposed that normalizing calprotectin might be a goal for truly deep remission, given its link with subclinical inflammation [7]. For example, if a patient’s joints are clinically quiet but calprotectin is still elevated, one might suspect residual synovitis and continue therapy rather than declare remission. On the flip side, a patient with high CRP but normal calprotectin might warrant investigation for non-RA causes of CRP elevation (infection, etc.), since calprotectin is more specific to joint inflammation. Such scenarios require clinical judgment; calprotectin is not yet an established target, but it can provide additional data to tailor treatment.

In summary, calprotectin is a useful biomarker for monitoring RA therapy, as it generally falls with successful treatment and rises with recurrent disease activity. It correlates with changes in joint inflammation even when CRP is unreliable. However, its role in predicting response to a new therapy is uncertain – current evidence suggests it offers no major advantage over CRP in that regard [15]. On the other hand, calprotectin shows promise in predicting relapse in patients under apparent control, potentially identifying those who still have subclinical disease activity. Further large-scale studies are needed, but calprotectin could become part of a precision medicine approach to decide when to intensify or taper RA treatment.

Limitations.

This review is subject to several limitations. First, heterogeneity exists among the included studies with respect to patient populations, disease duration, treatment regimens, and outcome definitions, which complicates direct comparisons. Second, variability in laboratory assays for calprotectin, including differences in platforms, sample types (serum vs plasma), and cut-off values, limits the generalizability of results and underscores the need for assay standardization. Third, although synovial fluid and fecal calprotectin provide additional insights, their clinical relevance in RA remains less well established, and most evidence derives from serum-based studies. Fourth, many reports are observational and cross-sectional in design, which precludes firm conclusions about causality or long-term prognostic value. Finally, although recent meta-analyses and cohort studies support calprotectin’s association with disease activity and therapeutic response, large-scale prospective trials and validation studies are still needed before calprotectin can be routinely implemented in clinical practice.

Conclusions

This review highlights calprotectin as a robust complementary biomarker of inflammation in adult rheumatoid arthritis, providing added value over conventional acute-phase reactants in reflecting true synovial disease activity. By synthesizing current evidence across biological matrices and clinical contexts, the manuscript underscores calprotectin’s particular usefulness in situations where CRP and ESR are unreliable or insensitive. While calprotectin should not be used in isolation, its integration into a multimodal assessment framework has the potential to improve disease monitoring and clinical decision-making. Further standardisation and prospective validation are required before routine implementation in clinical practice.

Competing interests

None declared.

Authors’ contribution

VZ conceptualized the review and drafted the manuscript. ER contributed to study design and critical revision. OB assisted with literature screening and data extraction. LG supervised the work and approved the final version. All authors read and approved the manuscript.

Acknowledgements and funding

No external funding

Provenance and peer review

Not commissioned, externally peer-reviewed.

Authors’ ORCID IDs

Vlada Zanosiev – https://orcid.org/0009-0004-6496-7058

Eugeniu Russu – https://orcid.org/0000-0001-8957-8471

Oxana Bujor – https://orcid.org/0009-0006-9072-9365

Liliana Groppa – https://orcid.org/0000-0002-3097-6181

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