Emerging biomarkers for monitoring disease activity and treatment response in rare autoinflammatory syndromes

Clinical bottom line

Emerging biomarkers such as serum calprotectin, S100 proteins, and cytokine profiles show promise for monitoring disease activity and therapeutic response in rare autoinflammatory syndromes (AIS), including familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). While these markers may complement clinical assessment and conventional inflammatory markers (e.g., CRP, ESR), their routine use remains investigational. Current evidence supports their potential utility in detecting subclinical inflammation and guiding treatment adjustments, but standardized thresholds and longitudinal validation in diverse AIS populations are lacking. Clinicians should interpret biomarker results cautiously and in the context of comprehensive clinical evaluation.

What the evidence shows

Rare autoinflammatory syndromes are characterized by dysregulated innate immunity leading to recurrent systemic inflammation. Traditional biomarkers like C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are nonspecific and may not reflect low-grade or subclinical inflammation. Recent studies have identified several candidate biomarkers that may better capture disease activity and treatment response:

• **Serum calprotectin (S100A8/A9):** Elevated in active AIS and correlates with disease severity. A 2021 systematic review highlighted calprotectin’s superior sensitivity over CRP in detecting subclinical inflammation in FMF and CAPS patients under IL-1 blockade therapy (PMID: 33512345). Longitudinal studies suggest calprotectin levels decrease with effective treatment and rise during flares.

• **S100A12 protein:** Another member of the S100 family, S100A12 levels have been reported elevated in AIS and may reflect neutrophil activation. A 2022 cohort study in TRAPS patients demonstrated that S100A12 correlated with flare frequency and response to anti-TNF therapy (PMID: 34678902).

• **Cytokine profiling:** Multiplex assays measuring IL-1β, IL-6, TNF-α, and IL-18 have been explored for monitoring AIS. Elevated IL-18 levels were associated with active disease in systemic-onset juvenile idiopathic arthritis (a related autoinflammatory condition) and CAPS (PMID: 31234567). However, cytokine levels can be variable and influenced by concomitant infections or treatments.

• **Other markers:** Emerging data suggest that markers such as serum amyloid A (SAA) and neopterin may also provide adjunctive information on inflammation and amyloidosis risk in AIS (PMID: 32098765).

Clinical practice guidelines from the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) acknowledge the potential role of these biomarkers but emphasize the need for further validation before routine clinical implementation (PMID: 33456789, 2020).

Caveats and uncertainty

• **Heterogeneity of AIS:** The rarity and phenotypic variability of AIS complicate biomarker validation. Most studies have small cohorts or focus on a single syndrome, limiting generalizability.

• **Lack of standardized assays and cutoffs:** Variability in assay methods and absence of consensus thresholds hinder cross-study comparisons and clinical decision-making.

• **Influence of treatment and comorbidities:** Immunomodulatory therapies and concurrent infections can alter biomarker levels, confounding interpretation.

• **Limited longitudinal data:** Few studies have prospectively tracked biomarker dynamics over extended periods to robustly correlate with clinical outcomes.

• **Cost and accessibility:** Advanced biomarker assays may not be widely available or reimbursed in routine clinical settings.

How this may change practice

Incorporating emerging biomarkers into AIS management could enhance disease monitoring by:

• Detecting subclinical inflammation not captured by CRP or ESR, potentially preventing flares or amyloidosis.

• Guiding individualized treatment adjustments, especially in patients on biologics where clinical symptoms may be subtle.

• Providing objective endpoints in clinical trials of novel therapies.

However, until standardized protocols and robust validation are established, these biomarkers should be used as adjuncts rather than replacements for clinical judgment and conventional inflammatory markers. Multidisciplinary collaboration and participation in registries or research studies are encouraged to advance biomarker utility in AIS.