How serum calprotectin is changing the way we understand rheumatic diseases

For decades, clinicians and researchers have sought more accurate, real-time indicators of inflammation to better diagnose, monitor, and predict outcomes in rheumatic diseases. While traditional markers like C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) have served as clinical cornerstones, they often lack specificity and responsiveness in certain patient populations. Now, an exciting biomarker is stepping into the spotlight – serum calprotectin (S100A8/A9) – offering clinicians a more sensitive tool to assess and manage inflammatory activity in both adult and pediatric patients.

In a recent SelectScience^® webinar, pediatrics rheumatologist Prof. Dr. Marija Jeluŝić, of the University of Zagreb, provided a comprehensive overview of the role of serum calprotectin in autoinflammatory diseases, including rheumatoid arthritis (RA), Still’s disease, vasculitis, and juvenile idiopathic arthritis (JIA). Drawing on clinical cases, emerging evidence, and decades of hands-on experience, Dr. Jeluŝić highlighted how serum or circulating calprotectin (S100A8/A9) is poised to redefine standards in rheumatology – particularly when it comes to early diagnosis, precise disease monitoring, and predicting flare-ups before symptoms are clinically apparent.

What is serum calprotectin, and why does it matter?

Calprotectin is a calcium-binding protein complex formed by S100A8 and S100A9, released in high amounts by neutrophils and monocytes at sites of active inflammation. As part of the innate immune system, it plays a key role in modulating the inflammatory response by promoting chemotaxis and phagocyte migration. But its significance extends beyond biology – it is now being recognized as a clinically useful biomarker of real-time inflammation, capable of providing insights beyond what CRP and ESR can reveal.

Unlike CRP, which is produced in the liver and can lag behind active inflammation, serum calprotectin originates at the site of inflammation, making it a more direct and responsive measure of immune activity. This nuance is crucial in diseases with rapid flare cycles, subclinical disease activity, or overlapping symptoms with infection – scenarios where timely clinical decisions can make all the difference.

“We often see cases where CRP is within normal limits, yet the patient is clinically flaring,” Dr. Jeluŝić said. “In those moments, calprotectin gives us the clarity we need to act early.”

Diagnosing autoinflammatory diseases with greater confidence

In the diagnostic setting, serum calprotectin is especially valuable in cases of fever of unknown origin (FUO) – a common yet challenging presentation in both children and adults. Many autoinflammatory diseases such as systemic JIA, adult-onset Still’s disease (AOSD), and vasculitis can mimic infection, with overlapping signs like fever, fatigue, and elevated acute-phase reactants.

Dr. Jeluŝić presented several clinical scenarios in which serum calprotectin is instrumental in identifying inflammatory disease when initial lab results and imaging suggest other clinical culprits. “In children with systemic JIA who present with prolonged fever, rash, and joint swelling, serum calprotectin can help us confidently differentiate between an autoinflammatory process and an infection,” she explained.

She emphasized that calprotectin levels tend to be significantly higher in active Still’s disease and systemic JIA than in viral or bacterial infection – offering a diagnostic edge in urgent care or emergency settings, where swift decisions about immunosuppressive therapy versus antibiotics must be made.

Tracking rheumatic disease activity with greater precision

One of the standout benefits of serum calprotectin is its strong correlation with clinical disease activity. As Dr. Jeluŝić described, patients with RA or JIA often present with fluctuating symptoms that are difficult to capture with single-point CRP or ESR measurements. In contrast, serum calprotectin levels tend to track more consistently with clinical outcomes, joint imaging, and treatment response.

In patients receiving biologic therapies – particularly TNF inhibitors or IL-6 blockers – calprotectin appears to serve as a more responsive biomarker of inflammation than traditional markers. Dr. Jeluŝić noted that it can even reflect subclinical inflammation, alerting physicians to smoldering disease activity that might otherwise go unnoticed.

“Sometimes a patient feels fine, CRP is normal, but calprotectin tells another story,” she said. “It allows us to catch disease activity before it escalates – before joints are damaged or systemic complications arise.”

She also highlighted the biomarker’s potential to inform treatment tapering decisions. In patients entering remission, low or steadily declining calprotectin levels may support the decision to reduce or pause medications, while persistently elevated levels may indicate that continued treatment is warranted.

A predictive tool for flare risk and disease prognosis

Beyond current inflammation, serum calprotectin may also act as a predictive marker for future disease flares. Studies have shown that elevated levels of calprotectin during periods of clinical remission can foreshadow relapse, especially in JIA and RA. This forward-looking attribute offers a powerful tool for clinicians aiming to prevent flares, reduce long-term medication burden, and personalize treatment strategies.

“Imagine being able to forecast a disease flare before the patient even feels unwell,” Dr. Jeluŝić said. “That’s the direction we’re heading with calprotectin-guided care.”

She also touched on the potential for serum calprotectin to contribute to risk stratification – helping determine which patients are likely to respond to specific therapies and which might require closer monitoring.

Pediatric-specific considerations and reference values

As a pediatric specialist, Dr. Jeluŝić emphasized the importance of age-adjusted interpretation of calprotectin levels. Because serum calprotectin levels can be naturally elevated in infants and young children due to higher innate immune activity, clinicians must rely on age-specific reference ranges when using the biomarker in pediatric populations.

Despite this, she noted that serum calprotectin is proving invaluable in diagnosing and monitoring systemic JIA – particularly in early stages where joint symptoms may be subtle or absent. She shared data and experience from her own clinical practice, where calprotectin has helped identify subclinical inflammation and adjust treatment even in the absence of classic clinical signs.

New frontiers for calprotectin

The webinar concluded with a look toward the future. Calprotectin’s potential applications continue to expand, particularly in the context of COVID-19–related inflammatory syndromes, autoimmune-autoinflammatory overlap diseases, and biologic response prediction. Additionally, researchers are investigating how serum calprotectin could complement or even replace current biomarkers in treat-to-target protocols for RA and JIA.

“Ultimately, we’re moving toward more nuanced, personalized approaches to rheumatologic care,” Dr. Jeluŝić said. “And calprotectin is helping to lead that transformation.”

Still, widespread adoption depends on greater awareness among clinicians, the establishment of standardized reference ranges, and continued education on how best to integrate the biomarker into existing diagnostic workflows.

Audience questions highlight real world impact

The Q&A portion of the webinar revealed just how curious and engaged clinicians are about integrating calprotectin into daily practice.

Q: Can calprotectin replace CRP in clinical workflows?
Dr. Jeluŝić clarified that the intention is not for calprotectin to replace CRP, but rather to complement it. “It’s a useful addition when CRP doesn’t align with the clinical picture,” she said. “Used together, they give a fuller understanding.”

Q: How frequently should calprotectin be tested?
Testing frequency depends on disease severity and treatment goals. In active disease or when adjusting therapy, more frequent monitoring may be appropriate. “We often measure it every few weeks during flares or treatment changes,” Dr. Jeluŝić advised.

Q: Is it useful in non-rheumatic inflammatory conditions?
Yes. While this webinar focused on autoinflammatory diseases, calprotectin has shown promise in inflammatory bowel disease, infections, and certain cancers. However, interpretation should always be contextualized.

To explore case examples, view clinical data, gain P.A.C.E and ACCENT credits, and hear the full presentation from Prof. Dr. Jeluŝić, you can watch the full webinar on demand here.