Giant cell arteritis (GCA) is an immune-mediated ischemic condition and is the most common form of systemic vasculitis in patients aged ≥50 years (1). It belongs to the group of large vessel vasculitis according to the 2012 International Chapel Hill Consensus Conference nomenclature (2). Previously known as temporal arteritis, which is now considered a form of GCA, the disease itself is now viewed more broadly. So far, no uniform classification of the disease has been established. Currently, more and more authors are inclined to the view that we should speak of a GCA-polymyalgia rheumatica (PMR) disease spectrum (3), distinguishing between cranial GCA, extracranial GCA, generalized inflammation, and PMR. It should be noted that nearly 50% of GCA patients exhibit PMR clinical presentations, while nearly 20% of PMR patients also have concomitant GCA manifestations (4). Glucocorticoids (GCs) have long been the treatment of choice for GCA, but recent studies have shown that additional agents such as tocilizumab, methotrexate, and leflunomide are effective steroid-sparing alternatives (5–7).

Recent advancements in imaging technologies, classification criteria, and novel therapies have improved diagnosis and treatment. However, there are still many unknowns regarding relapse monitoring and long-term treatment strategies. In patients with GCA in clinical remission, long-term clinical monitoring is strongly recommended by the 2021 ACR guidelines for the management of giant cell arteritis (5). This is the only strong recommendation in this paper, reflecting both the minimal risk of routine surveillance and the potentially severe consequences of inadequate monitoring – namely aneurysmal dissection or rupture, and vascular stenosis leading to ischemia. The optimal frequency and duration of monitoring remain unknown. Clinical monitoring may include history, physical examination, and laboratory and imaging studies. Imaging is becoming increasingly important in diagnosing and assessing disease activity. Arterial ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) are used for this purpose; however, all of them have limitations, and when used alone, they are not always sufficient for this purpose (8).

Laboratory monitoring of GCA is based on the evaluation of traditional inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). According to ACR guidelines, if inflammatory markers are elevated alone, clinical observation and monitoring without intensification of immunosuppressive treatment are conditionally recommended. This may justify more frequent clinical check-ups and the use of imaging studies (4). The BSR guidelines differ in this respect, making the reduction of glucocorticoid (GC) doses dependent on the normalization of inflammatory markers (6). EULAR guidelines are rather vague on this matter. Cases of elevated inflammatory markers alone, suggest observation and monitoring rather than immediate intensification of immunosuppressive therapy unless additional clinical or imaging signs suggesting disease activity occur (7).

An additional challenge is that the use of IL-6 inhibitors alters the natural course of inflammation, making it more difficult to track the true state of the disease using traditional inflammatory markers and clinical images. IL-6 inhibitors can significantly reduce symptoms of inflammation, such as fever, pain, and changes in laboratory test results (e.g., CRP).

As a result, there is an ongoing search for biomarkers of GCA activity. New blood biomarkers that are less dependent on the IL-6 axis, such as IL-23, B cell-activating factor, osteopontin, and calprotectin, are being investigated. One of the most promising markers is serum calprotectin (CLP) (9). CLP is a heterodimeric complex (S100A8/S100A9, also known as myeloid-related protein 8/14 [MRP8/14]) formed by two binding proteins belonging to the S100 protein family and is produced mostly by neutrophils, monocytes, and early differentiated macrophages (10). CLP is a recognized marker in inflammatory bowel diseases (IBD). Determination of fecal calprotectin concentration is helpful both in diagnosing and monitoring IBD activity. However, its important biological role in inflammation, immune cell recruitment, and tissue damage, which are processes that underlie vascular injury, means that it may also find application in GCA and other vasculopathies (10, 11). In this article, we discussed the biological role of CLP in GCA, taking into account the pathophysiology of the disease, as well as literature data and perspectives on the clinical utility of calprotectin in diagnostics, differentiation of clinical forms, and monitoring disease activity of GCA.

The S100 family, to which CLP belongs, comprises 25 proteins in humans containing a specific Ca²⁺-binding motif (helix-loop-helix), called the EF-hand, which tightly responds to Ca²⁺ levels and is thus exclusively implicated in intracellular and extracellular regulatory activities (10). Extracellularly released CLP can be involved in inflammation, immune cell recruitment, and tissue damage, all contributing to the vascular damage seen in the pathogenesis of GCA and other vascular diseases (10). Many studies demonstrated elevated levels of CLP in sera of GCA patients (12–15). A summary of the possible role of CLP in the pathogenesis of GCA is presented in Figure 1 .

Secreted CLP functions as a Damage-associated Molecular Pattern (DAMP) or alarmin, released in response to cellular stress or tissue injury, activating the innate immune system during non-infectious inflammatory processes. CLP interacts with a variety of receptors, including Toll-like receptor 4 (TLR4), the receptor for advanced glycation end products (RAGE), and CD33. This interaction leads to the activation of key signaling pathways, such as MAPK/NF-κB and AP-1, culminating in the production of proinflammatory cytokines, including IL-6, TNF, and IL-1, chemokines and generation of reactive oxygen species (ROS) (11). These molecules are notably elevated in GCA and other forms of vasculitis. The receptors for CLP are expressed on various innate immune cells, such as neutrophils, monocytes/macrophages, and dendritic cells (DCs), as well as on non-immune cells, including endothelial cells and smooth muscle cells that are critical for blood vessel formation. To date, no studies have investigated the expression of RAGE or CD33 in patients with GCA, and the available study on TLR4 did not demonstrate a difference in its expression between GCA patients and controls (16). Furthermore, TLR4 gene polymorphisms were not associated with the occurrence of GCA itself nor did they predispose to any of the clinical forms of GCA (17, 18). This may suggest that only disturbed levels of CLP but not their receptors play a role in GCA pathogenesis.

Recent evidence has highlighted a previously underappreciated role for neutrophils in the pathogenesis of GCA. Immunohistochemistry staining directly demonstrated co-expression between CLP and markers for macrophages (CD68 and CD163) and neutrophils (CD15) in temporal artery biopsy (TAB) of GCA patients, suggesting an important role of innate immune cells in initiating inflammatory responses which results in inappropriate tissue remodeling (12, 13). CLP is also present in neutrophil extracellular traps (NETs) - DNA-protein structures released by neutrophils that trap pathogens, but can also promote inflammation and tissue damage. Studies have demonstrated NETs in GCA patients near the vasa vasorum (19). NETs may promote immune-mediated thrombosis and tissue injury in GCA, as intraluminal thrombosis is present in up to 20% of positive biopsies (20). Moreover, increased circulating NETs in GCA patients were also found, supporting systemic neutrophil activation (21). However, the functional relevance of CLP in NETs remains to be fully elucidated, warranting further investigation.

The role of T cells in the pathogenesis of GCA is well established (20, 22, 23). CLP may represent a mechanistic link between innate and adaptive immunity through its effects on T cells. Upon binding to its receptors on innate immune cells CLP promotes the recruitment and activation of T cells within the arterial wall. The previously described effect of CLP on the production of proinflammatory cytokines, including IL-6, TNF-α, and IL-1β, primarily via activation of the NF-κB pathway, influences T cells. These cytokines play a role in T cell recruitment and differentiation, particularly the polarization of naïve CD4⁺ T cells toward Th1 and Th17 phenotypes, seen in the vascular lesions of GCA (20, 22). The aforementioned interaction of CLP with TLR4 also contributes to T-cell response, as evidenced in murine models showing increased expression of markers related to T-cell recruitment (TCR) and activation (CD40L, LTα, IFN-γ) (24). Additionally, CLP contributes to the induction of autoreactive CD8⁺ T cells by acting as a costimulatory enhancer alongside CD40/CD40L signaling, thereby promoting loss of T cell tolerance (25). The regulatory effects of CLP, however, are cell-type dependent: DCs from S100A9-deficient mice exhibit an exaggerated proinflammatory profile and an enhanced capacity to induce T cell proliferation, while macrophages lacking S100A9 show no such differences in their response to TLR ligands (26). Moreover, CLP acts as an endogenous ligand for CD69 on regulatory T cells, supporting their differentiation and contributing to the maintenance of immune homeostasis (27).

Due to its important role in the pathogenesis of autoimmune inflammatory rheumatic diseases (AIIRD) and the fact that CLP is easily detectable in blood serum and synovial fluid, it has recently gained prominence as a promising biomarker for diagnosis, assessment of disease activity, and predicting treatment response/disease relapse in an increasing number of AIIRDs (28, 29).

As in the case of other systemic vasculitis, in recent years there has been an increasing number of studies indicating the possible clinical use of CLP in GCA - in diagnosis, including differentiation of the disease form, and as a marker of disease activity, helping to monitor the effectiveness of treatment and make therapeutic decisions. The summary of the research is presented in Table 1 .

The important biological role of CLP in the pathophysiology of GCA makes it a potential therapeutic target. Although CLP itself has not yet been a primary target in therapeutic strategies for GCA, small molecules that inhibit CLP formation have progressed to Phase 2 and 3 clinical trials in other indications. These investigational therapies target a variety of cancers and inflammatory conditions, including multiple myeloma, multiple sclerosis, prostate cancer, uveitis, and sepsis-induced myocardial dysfunction. Notable agents in this class include laquinimod (ABR-215062), tasquinimod (ABR-215050), and paquinimod (ABR-215757). For example, laquinimod (ABR-215062) has been shown to reduce proinflammatory cytokines activity and ROS formation resulting in improvement of myocardial dysfunction (54), protecting caudate volume loss in Huntington’s disease (55), and improving the effect of clinical remission in Crohn’s disease (56). Tasquinimod (ABR-215050) by blocking S100A9 activity was able to sensitize cancer cells for apoptosis (57, 58). Paquinimod (ABR-215757) was proven to inhibit skin fibrosis in systemic sclerosis patients (59) and reduce disease activity in experimental lupus (60). Overall, these examples of CLP-neutralizing therapies in cancer and inflammatory conditions may also hold promise for the future treatment of GCA, potentially leading to reduced immune cell infiltration, downregulation of proinflammatory cytokines, and inhibition of blood vessel remodeling.

GCA remains a complex immune-mediated vasculitis with evolving diagnostic and therapeutic strategies. Despite advancements in imaging, classification, and treatment, challenges persist in diagnosing, disease monitoring, and relapse prevention. CLP has emerged as a promising biomarker for GCA, with potential utility in diagnosing disease, assessing activity, and guiding treatment decisions – especially in patients receiving IL-6 inhibitors. Possible further studies evaluating the usefulness of CLP may focus on better diagnosis, e.g. evaluating the correlation of CLP with south-end giant cell arteritis probability score or CLP differential value in different forms of GCA-PMR spectrum diseases. Further research is also required on the more comprehensive assessment of disease activity with CLP, e.g. taking into account newer scales such as Large-Vessel Vasculitis Index of Damage. It would also be worthwhile to study the predictive value of CLP in the assessment of subclinical inflammation of large vessels (taking into account the latest imaging studies) and their significance, whether it predicts disease recurrence, in a larger number of patients. Expanding our understanding of CLP in GCA could enhance precision medicine approaches, ultimately improving patient outcomes.