1. 2024;27;495-506A Review of Etiological Biomarkers for Fibromyalgia and Their Therapeutic Implications
   Narrative Review
   Marc Russo, MBBS, Danielle Santarelli, PhD, Peter Georgius, MBBS, and Paul J. Austin, PhD.

BACKGROUND: Fibromyalgia is a complex condition that has long puzzled the medical community. Hypotheses to explain the chronic widespread pain associated with the disease have evolved significantly over the years. However, research efforts to identify disease-specific biomarkers and develop effective treatments have been largely unsuccessful.

OBJECTIVES: The goals of this study were to review potential etiological biomarkers for fibromyalgia, focusing on micro-inflammation and metabolic syndrome, and to discuss the clinical implications of the review findings.

STUDY DESIGN: A narrative review.

METHODS: Relevant literature was obtained via Medline/PubMed, using the following search terms: fibromyalgia[ti] (“metabolic syndrome” OR “metabolic disease” OR biomarker*[ti] OR micro-inflammation OR sub-inflammation OR “low-level inflammation” OR “low-grade inflammation”). Results were filtered for the English language and screened for inclusion in the review.

RESULTS: Articles included in the review covered the topics of pain, immune response/inflammation, micro-inflammation, metabolic syndrome, gut dysbiosis, oxidative stress, and stress response. Various molecules have been proposed as pain biomarkers for fibromyalgia, including neurotransmitters, neuropeptides, growth factors, and cytokines with possible etiological relevance. Recent genome-wide expression profiling suggests connections among low-level inflammation, termed “micro-inflammation,” and the upregulation of genes involved in antibacterial and innate immune system response as well as those involved in clinical features, including high body mass index (BMI) and comorbid depression, in a subgroup of fibromyalgia patients. A set of 5 differentially expressed inflammatory genes have been identified as potential biomarkers of a micro-inflammation fibromyalgia subtype. Proposed triggers of micro-inflammation include bacterial disease and gut dysbiosis. Metabolic syndrome may be causative or consequential, while comorbid depression may be associated with dysbiosis and/or micro-inflammation through the gut-immune-brain axis. A potential new treatment approach based on this information has been proposed.

LIMITATIONS: External validation of potential etiological biomarkers is needed. Further investigations to ascertain the involvement of metabolic syndrome and gut dysbiosis and support the proposed treatment paradigm are warranted.

CONCLUSION: Fibromyalgia is likely the result of multiple causative factors, genetic and environmental. To date, no clear, reliable etiological biomarker for fibromyalgia has been identified. The considerable variability among patients suggests the presence of multiple disease subtypes with different pathophysiological mechanisms. Effective treatment therefore requires a multimodal, multidisciplinary approach that targets each individual patient’s pathophysiological features. The proposed treatment paradigm attempts to address multiple factors that have been implicated more recently in the development and maintenance of fibromyalgia, such as micro-inflammation, metabolic syndrome, and gut dysbiosis.

KEY WORDS: Fibromyalgia, biomarkers, inflammation, innate immune response, metabolic syndrome, dysbiosis, etiology