Policy Guidelines
Fibromyalgia (FM) is a condition characterized by chronic and diffuse non-inflammatory musculoskeletal pain. FM is often accompanied by fatigue, cognitive disturbances (“fibro fog”), psychiatric symptoms, and multiple other nonspecific somatic symptoms. Aside from the secondary symptoms, patients may at times experience abdominal and chest wall pain, irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and symptoms of autonomic nervous system (ANS) dysfunction. Despite this, FM is generally of unknown etiology and pathophysiology. However, FM should be considered as a diagnosis in patients experiencing idiopathic chronic pain for at least three months and is solely confirmed by a clinical, symptom-based assessment.
What adds to the controversial and mysterious nature of the condition is that it depends on subjective symptoms. On a normal physical examination, patients often appear well and do not show abnormalities other than “widespread soft tissue tenderness” with normal laboratory and radiologic studies, making it a common but elusive diagnosis. However, a history of other medical conditions that cause musculoskeletal pain can coexist with or mimic FM like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and thyroid disease. Medical history can support a FM diagnosis. FM is more commonly diagnosed in women than men. The prevalence of FM in the United States and other countries is about two to three percent and incidence tends to increase with age. FM can also be diagnosed in adolescents in the form of juvenile primary fibromyalgia, and it is confirmed mostly symptomatically but based on slightly different diagnostic criteria for research and epidemiological purposes.
Fibromyalgia is categorized as a “disorder of pain regulation,” under “central sensitization”. This finding is supported by biochemical abnormalities that are oftentimes present in FM patients: low concentrations of metabolites of serotonin (5HT) and noradrenaline (NA), and high concentrations of substance P and nerve growth factors. Patients are more sensitive to central nervous system inputs of pain, and those with FM at times can experience symptoms like those suffering from other central pain disorders, like migraines, IBS, and temporomandibular joint disorder (TMD). Reduced 5HT and NA may actually account for the widespread pain symptoms by contributing to the dysfunction of endogenous systems that inhibit pain sensation.
Contrary to the established findings published about FM, recent research has demonstrated that there is a possible genetic basis to the disease progression; up to 50% of disease risk can be attributed to candidate genes. There also appears to be a strong familial predisposition to FM, although it is suspected to have a more polygenic mode of inheritance. However, there is no singular definitive gene that directly causes FM; several genes under consideration include SLC64A4, TRPV2, MYT1L, and NRXN3. Single nucleotide polymorphisms (SNPs) in the SLC64A4 gene, which encodes a sodium-dependent serotonin transporter, has been associated with both FM and TMD. SLC64A4 mutations that cause increased serotonin reuptake have been associated with high levels of depression and psychological disorders, as well as “SCL-90 [Symptom Checklist-90 for psychopathological disorders] scores for somatic awareness and anger, TPQ [tridimensional personality questionnaire] harm avoidance trait, increased salivary cortisol level, [and] increased leukocyte count”. TRPV2 (transient receptor potential vanilloid channel 2) gene is needed for not only cell cycle progression, growth, and differentiation of hematopoietic stem cells and innate immunity, but also the pain threshold due to its presence in the mechanoresponsive and thermo-responsive neurons in the dorsal root and trigeminal ganglia. Genetic correlations in FM between mutations in SLC6A4 and TRPV2, which encodes a calcium-permeable channel that is heat-activated and modulates many cellular functions, are further supported by linkage analysis done with FM to the chromosome 17p11.2-q11.2 region, which happens to house the two genes.
Docampo et al. (2014) discovered that the rs11127292 polymorphism in the MYT1L (myelin transcription factor 1 like) gene, which is critical in the process of neuronal differentiation and has historically been associated with neuropsychiatric disorders, and an intronic CNV (copy number variant) in the NRXN3 (neurexin 3) gene, which is involved in signal transmission by promoting synapse stability and function, affect the central nervous system (CNS) aspect of FM as well.
Studies have also examined the differences in other allelic frequencies and influence of genetics on the sequelae of FM progression. Smith et al. (2012) identified significant variations in allelic frequency of GABRB3 (rs4906902), TAAR1 (rs8192619), and GBP1 (rs7911) between FM patients and controls. TAAR1 was demonstrated to alter dopamine bioavailability and function, which may cause the increased pain sensitivity seen in FM. RGS4, CNR1, and GRIA4 were implicated in other cohorts from the study by Smith et al. (2012), and are genes primarily involved in mechanisms of analgesia and central sensitivity as well. RGS4, which is expressed in the CNS regions like the dorsal horn of the spinal cord and the locus coeruleus, influences opioid receptor function when overexpressed. CNR1, which encodes the CB-1 cannabinoid receptor, has been indirectly utilized in FM treatment by the cannabinoid receptor agonist nabilone. Low CNR1 expression and thus low CB-1 receptor activity may pose as a strong candidate for future testing, as several FM patients have increased circulating anandamide, an endocannabinoid, which has been hypothesized to underlie the pain in conditions like FM. Alterations to the GRIA4 gene affect AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, which play roles in the pain and comorbidities associated with FM.
Another gene commonly associated with FM is the COMT (catecholamine o-methyl transferase) gene. Though not directly affecting disease presentation, the V158M variant may contribute to subsequent depression, anxiety, and disability in many FM females. Mutations in the COMT gene are more closely linked to “pain catastrophizing, increased pain level during elevated pain attention, thermal and pressure sensitivity, psychological distress, increase number of tender points in TPC [tender point count], pain and positive affect interaction, and FIQ [fibromyalgia-impact questionnaire]-defined pain, fatigue, sleep, disturbance, morning stiffness, and disability”. Similarly, mutations in the HTR2A (5-hydroxytryptamine receptor 2A) gene, which encodes for its receptor, 5-HT2A, contributed to lower levels of total 5-HT in serum and CSF of FM patients. The phenotype in FM more closely relates to psychological facets of FM – including reduced perception of environmental quality, “increased SCL-90-R total score and subscales scores for somatic awareness, anxiety, psychosis, obsessive-compulsive behavior, hostility, global severity index, interpersonal sensitivity, phobic anxiety, [and] depression”.
Research has also demonstrated the role of epigenetics in FM phenotype and progression. Ciampi de Andrade et al. (2017) investigated DNA methylation states in samples obtained from FM cases and healthy controls, and found that the majority (1042 genes, 65%) of the differently methylated genes between the two were mostly hypomethylated. These genes were involved in “transduction and calcium signaling, MAPK signaling pathway, regulation of actin cytoskeleton endocytosis, and neuroactive ligand-receptor interaction pathways,” and the sites that were identified were involved in DNA repair, immune system response and regulation, and membrane transport. Additionally, circulating miRNAs obtained from cerebrospinal fluid (CSF) and serum samples were found to be associated with many of the clinical symptoms of FM, including pain and fatigue, alterations in energy metabolism and growth, alterations in pain threshold, and sleep disturbance.
Proprietary Testing
Some researchers have opted for a proteomics approach to identify individuals with FM. Among females with FMS, Han et al. (2020) discovered dysregulated proteins and mechanisms associated with an FM diagnosis. They propose a panel of methyltransferase-like 18 (METTL18), immunoglobulin lambda variable 3-25 (IGLV3-25), interleukin-1 receptor accessor protein (IL1RAP), and putative V-set and immunoglobulin domain-containing like protein (IGHV1OR21-1) to differentiate FM from healthy controls. This conclusion was drawn from using a decision tree model that yielded an accuracy of 0.97. Collectively, they offered 100% detection sensitivity in their training cohort, and a specificity of 88%.
Genova Diagnostics has also released the NutrEval FMV® Profile, which is a “blood and urine profile that evaluates over 125 biomarkers and assesses the body's functional need for 40 antioxidants, vitamins, minerals, essential fatty acids, amino acids, digestive support, and other select nutrients.” NutrEval® aims to provide insight into conditions such as depression, anxiety, certain inflammatory conditions, and chronic pain syndromes. While there are no peer-reviewed studies published to confirm either the analytical or clinical utility of this particular proprietary test, researchers have delved into the biomarkers that comprise this assay. The aforementioned research on COMT proves relevant in the genomics component of this test. The clinical utility for the NutrEval® Profile is particularly pertinent to the chronic pain aspect. In patients with chronic pain, it was found that quinolinic acid, pyroglutamic acid (indicator of glutathione depletion), xanthurenic acid (indicator of vitamin B6 insufficiency), 3-hydroxyropyl mercapturic acid (acrolein metabolite), and methylmalonic acid (indicator of vitamin B12 deficiency) were all elevated to a certain degree among patients experiencing chronic pain. Seventy-seven percent of patients with chronic pain all had at least one abnormal biomarker. This demonstrates that understanding the role of nutrition metabolism is necessary for delineating the underlying processes of FM, a chronic pain condition, but additional research is needed.
Clinical Utility and Validity
Currently, most, if not all, of the FM diagnoses are solely clinical. Judgment is made subjectively and dependent on guidelines to conclude if subjective symptoms translate to FM. The sensitivity and specificity of utilizing the 2016 ACR guidelines, when compared to the 1990 criteria in a referral care setting, are 71% and 60%, respectively, with a positive predictive value of 85% and a negative predictive value of 39%. These statistical measures evidently prove that there need be more sensitive and specific measures beyond clinical symptoms for diagnosis of FM.
The clinical utility of an FM diagnosis extends beyond genetic testing and biomarkers; FM is also found concurrently among those with primary immunodeficiency and autoimmune diseases, such as RA, SLE, and Sjögren Syndrome (SS). Confirming an FM diagnosis could aid in explicating the additional complications found in RA and SLE, such as “alternating constipation and diarrhea, urinary frequency, diffuse paresthesias, and cognitive difficulties.” The converse also holds true – diagnoses of SS could prompt possible FM diagnoses as well, as seen in the cases of seeing sicca symptoms and TPC of six (though not necessary with 2016 ACR guidelines).
Janssen et al. (2021) conducted a review that identified the polymorphisms related to FM and the respective clinical characteristics. From 27 articles, they found the relevant genes to be MTHFR, RGS4, MYT1L, TACR1, SCN9A, DRD3, ADRB2, IL-4, HLA-DRB1, EDN1, CNR1, TAAR1, OPRM1, ADRA1A, ADRB3, BDNF, GRIA4, HTR3A, HTR3B, HTR2A, SERPINA 1 or A1AT, NRXN3, GCH1, MEFV, TRPV3, SLC6A4, ACE I/D, TSPO, COMT, and MAOA. Additionally, “73.33% of the genes related to FM were also associated with some psychological disorders, such as anxiety, depression, schizophrenia, and obsessive and compulsive disorder, and 40.00% with pain sensitivity and/or migraine, besides other disorders associated (drug addiction, autoimmune disorders, circulatory problems, and metabolic alterations).” Of note, SLC6A4, HTR3A, HTR3B, and HTRA genes were associated with serotonergic regulation, chronic pain conditions, and anxiogenic situations; COMT was related to FM risk and increase in pain severity, increased likelihood of psychological disorders like “depression, anxiety and schizophrenia, alcoholism, opioid addiction, and eating disorders; BDNF was associated with hyperalgesia in FM; and TACR1 was related to dementia and fatigue. As for treating FM, Janssen et al. (2021) also found that TAAR1, RGS4, CNR1, GRIA4 may be considered as targets. These collective findings continue to demonstrate the comorbidities associated with FM, and how understanding the genetic bases may aid in preventing and treating additional sequelae.
Kendler et al. (2022) studied the familial genetic risk for functional somatic disorders including internalizing disorders, chronic fatigue syndrome, IBS, and FM. The study included 5,829,186 individuals in Sweden. The authors used a novel method that assessed aggregated risk in first to fifth degree relatives and adjusted for cohabitation. “Patients with FM carry substantial genetic risks not only for FM, but also for pain syndromes and internalizing, autoimmune and sleep disorders.” Overall, patients with FM had a unique family risk genetic score with elevated genetic risk across other disorders; the was a similar but less marked pattern of genetic risks in patients of other functional somatic disorders. The authors suggest that the genetic risk score for FM differentiated it from classic autoimmune disorder and internalizing disorder.
Guidelines and Recommendations
American Pain Society
The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) partnership with the Food and Drug Administration (FDA) and APS created the ACTTION-APS Pain Taxonomy (AAPT) to help standardize clinically useful and consistent diagnoses of chronic pain disorders. First and foremost, all patients must have chronic pain to be diagnosed with FM. The working group members raised a concern of defining FM-pain as by the 1990 ACR criteria (CWP – chronic widespread pain) or the ACR 2010/2016 criteria of multisite pain (MSP), which were distinguished in count (MSP) versus anatomical distribution (CWP) of pain.
To facilitate identifying FM in clinical practice and in research, the AAPT core diagnostic criteria for FM are as follows:
- “MSP defined as 6 or more pain sites from a total of 9 possible sites [head; left arm; right arm; chest; abdomen; upper back and spine; lower back and spine, including buttocks; left leg; and right leg]
- Moderate to severe sleep problems OR fatigue
- MSP plus fatigue or sleep problems must have been present for at least 3 months.”
This guideline did not mention genetic testing for FM.
American College of Rheumatology (ACR)
In 2016, the ACR published revisions to their 2010/2011 guidelines on preliminary diagnostic criteria for fibromyalgia and measurements of symptom severity. To satisfy a diagnosis of fibromyalgia, a patient must have:
- “Widespread pain index (WPI) ≥ 7 and symptom severity (SS) scale score ≥ 5 or WPI 4-6 and SS scale score ≥ 9.
- Generalized pain, defined as pain in at least 4 or 5 regions, must be present. Jaw, chest, and abdominal pain are not included in generalized pain definition.
- Symptoms have been present at a similar level for at least 3 months.
- A diagnosis of fibromyalgia is valid irrespective of other diagnoses. A diagnosis of fibromyalgia does not exclude the presence of other clinically important illnesses.”
The table below obtained from the ACR’s publication regarding ascertainment of WPI and SS is shown.
Ascertainment
(1) WPI: note the number of areas in which the patient has had pain over the last week. In how many areas has the patient had pain? Score will be between 0 and 3.