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Abstract

Fibromyalgia presents a clinical enigma as its pathophysiology is not well understood and its symptoms are nonspecific and overlap with many disorders, making its diagnosis a challenge for clinicians and researchers. Efforts have been made to develop a set of diagnostic criteria for this disorder. However, these criteria rely heavily on expert clinician opinion and produce a large heterogeneity within the diagnosed population. With no present specific technique reflecting the underlying pathophysiology of fibromyalgia, a definitive diagnosis of fibromyalgia remains elusive. This review discusses some problems and challenges associated with fibromyalgia diagnosis and presents some novel findings on the pathophysiological nature of fibromyalgia.

Keywords

Fibromyalgia diagnostic criteria

Introduction

Fibromyalgia presents a clinical enigma. Its pathophysiology is not well understood and its symptoms are nonspecific and overlap with many disorders, making its diagnosis a challenge for clinicians and researchers. Efforts have been made to develop a set of diagnostic criteria for this disorder. Classification criteria were developed in 1990 and diagnostic criteria were implemented in 2010 by the American College of Rheumatology (ACR). The 2010 criteria were modified in 2011 and further modifications to the criteria were introduced in 2016,^1–4 these are currently the most accepted methods of fibromyalgia diagnosis. These criteria rely heavily on expert clinician opinion and are not definitive diagnostic tests, therefore they produce large heterogeneity within the diagnosed population. Additionally, many physicians are not compliant with the diagnostic criteria and do they do not have a comprehensive understanding of the disorder.^5–8 They rely on their clinical acumen and judgment for diagnosis, introducing additional variability into the diagnosed population.

The 1990 ACR diagnostic criteria suggest that widespread pain is the main classifying and clinical characteristic of fibromyalgia.¹ The 1990 criteria were revisited in 2010 to account for patients who present less muscle tenderness and more secondary symptoms, in addition to addressing poor physician use of the tender point count. The 2010 criteria introduced a new group of patients who present with higher severity of secondary symptoms such as depression, poor sleep, cognitive symptoms, and somatic symptoms with a minimum of three tender regions.^2,4 The 2016 revision necessitated a minimum of four tender regions, one in each of four quadrants in the body, with a high symptom severity score (>9) for a diagnosis of fibromyalgia. These changes introduce more heterogeneity into the diagnosis of patients with fibromyalgia as some may present with high affective distress and little muscle pain, and others may present with high levels of muscle pain and little affective and sleep distress. Therefore, a substantial barrier for fibromyalgia diagnosis is the lack of specificity of its diagnostic signs and symptoms. The specific features of the diagnostic criteria for fibromyalgia are themselves common across a wide range of conditions, beyond even immediate differential diagnoses for fibromyalgia. Most patients presenting with one or more of muscle aches and pain, fatigue, poor sleep and mild cognitive symptoms still may not have a formal diagnosis of fibromyalgia. It is also possible that the current fibromyalgia population is composed of patients who may present primarily with depression, a sleep disorder, a cognitive affective disorder or a somatic disorder along with a limited amount of muscle aches and pain.^2–4 Symptoms such as pain, fatigue, sleep disturbances, cognitive difficulties and depression are nonspecific and can also be caused by different pathophysiological mechanisms.

Current literature shows that the tender point count criterion has been shown to poorly differentiate between fibromyalgia and other pain disorders such as myofascial pain syndrome.^9,10 Gerwin and colleagues^11,12 also report the clinical presence of tender points in 79% of patients with myofascial pain syndrome and an overlap with fibromyalgia of approximately 40%. Additionally, the tender point count is typically higher in women relative to men, therefore more women are likely to be diagnosed with fibromyalgia.^13,14 Jones and colleagues¹⁵ found that more women were diagnosed with fibromyalgia relative to men using the 1990, 2010 and modified 2010 criteria. However, the prevalence of women with fibromyalgia relative to men using the 1990 criteria, which utilizes only the tender point count, was 13.7 fold and was lower for the other criteria. Several studies have delineated clinical subgroups among patients with fibromyalgia diagnosed with the 1990 criteria, which is considered the most specific definition of fibromyalgia, suggesting that the 1990 criteria diagnose a heterogeneous spectrum of patients.^16–18 The severity of the variables assessed in the subgroups ranged from experiencing psychological wellbeing, low pain and little disability to displaying physiological (neuroendocrine, immune, metabolic) dysregulation, high anxiety, as well as severe pain and disability. These presentations could theoretically have been the result of various pathophysiological mechanisms. Therefore, the 2010, 2011 and 2016 criteria likely diagnose a more heterogeneous group of individuals relative to the 1990 criteria.^16–18

Methodological problems associated with the accepted classification and diagnostic criteria

There are some methodological problems associated with the creation of the 1990 classification criteria and subsequently the 2010, 2011 and 2016 criteria that may lead to the diagnosis of a heterogeneous group of patients. Figure 1 highlights the factors that are contributing to the diagnostic heterogeneity.

Figure 1.

Factors contributing to diagnostic heterogeneity in clinical groups.

The 1990 classification criteria were developed through consensus from fibromyalgia experts using clinical observations and assessments.¹ Criteria developed through expert consensus increases the chances for misdiagnosis because they are limited to information available to the expert at that time, which may not be comprehensive, and is biased by their internal concept of the disorder which is dependent on their clinical experience.¹⁹ These types of criteria also vary across time and countries, where different representations of the same condition are accepted.¹⁹ Therefore, the sensitivity of 88.4% and specificity of 81.1% reported for the 1990 criteria may not have been accurate. The 2010 criteria were developed using the 1990 criteria as the reference standard.² Since the 1990 criteria are not a perfect diagnostic tool, the chance of error when developing the 2010 criteria increased. No statistical adjustments were used to determine accuracy rates reflective of the variability in physician and assessor judgments for both the 1990 and 2010 criteria. The 2011 modification used a different reference standard than the previous criteria, the National Data Bank of Rheumatic Diseases, in which the fibromyalgia population was determined by many different clinicians with undefined diagnostic methods. This further impacts the diagnostic accuracy of these criteria relative to the 2010 criteria. The 2016 criteria were an improvement of the 2010/2011 criteria, as they addressed shortcomings of the 2010/2011 criteria when validated relative to the 1990 criteria and clinical diagnosis. They are however still limited by the methodological shortcomings of the previous criteria. Table 1 contains methodological measures that should be comprehensively evaluated when developing a diagnostic method, and their application during the creation of the 1990 classification criteria, 2010, 2011 and 2016 diagnostic criteria based on the reports of Wolfe and colleagues.^1,2

Table 1.

Validity measures for the fibromyalgia American College of Rheumatology (ACR) diagnostic criteria, adapted from Lijmer and colleagues (1999)²⁰ and Reid and colleagues (1995)²¹.

Validity of diagnostic criteria	Accomplished by 1990 criteria	Accomplished by 2010 criteria	Accomplished by 2011 modification	Accomplished by 2016 criteria	Effect on accuracy and generalizability
Specify spectrum of evaluated patients	Yes	Yes	Yes	NA	Limits generalizability of studied sample to the stated demographics
Report test indexes for clinical subgroups	Yes	Yes	Yes	Yes	Indexes of accuracy provided represent the clinical error with the subgroup
Avoid verification bias	Yes	Yes	Yes	NA	Distorts indexes of accuracy
Provide numerical precision for indexes	No	No	No	No	Sensitivity and specificity values are numerically unstable with few or nonrepresentative patients
Specify test reproducibility	No	No	No	No	Limits the capability for the criteria to diagnose outside of the experimental setting
Avoided different reference tests	No	Yes	No	No	Adds variability to reported indexes
Avoided partial verification	Yes	Yes	Yes	NA	Adds variability to reported indexes
Blinded study	Yes	Yes	NA	NA	Prevents bias when determining whether index or reference tests are positive
Consecutive enrolment of patients	Yes	Yes	Yes	NA	If participants are not enrolled randomly or in a consecutive manner then there is a biased sample
Prospective	No	No	No	NA	Overestimation of diagnostic accuracy if test is evaluated in a group of patients already known to have the disease
Description of index test	Yes	Yes	Yes	Yes	Description of tests should be described with sufficient detail to allow for replication, validation, and generalization
Description of reference test	No	Yes	No	Yes	Description of tests should be described with sufficient detail to allow for replication, validation, and generalization

NA, not applicable.

Wolfe and colleagues⁴ reviewed studies that validated the 2010 and 2011 criteria against the 1990 criteria. They found several studies that accomplished this. Bidari and colleagues²² validated the 2010 criteria against the 1990 criteria by using dolorimetry to characterize tender points. They sampled 168 patients with fibromyalgia and 100 controls in Iran. They found that the 2010 criteria had 79.1% accuracy when using the 1990 criteria as the gold standard. Carrillo-de-la-Peña and colleagues²³ validated the Spanish version of the 2010 criteria against the 1990 criteria. They recruited 80 patients with fibromyalgia and 59 healthy control Spanish participants. They used algometry to identify tender points. They found an inter-criteria agreement of 0.73 between the 2010 and 1990 criteria. Usui and colleagues²⁴ assessed the validity of the Japanese version of the 2010 criteria relative to the 1990 criteria. They recruited 94 patients with 1990 defined fibromyalgia and 43 controls from Japan. They found a sensitivity of 82% when comparing the 2010 criteria with the 1990 criteria. There is a general decrease in accuracy measures when comparing the 2010/2011 criteria with the 1990 criteria.⁴

The current challenge facing researchers and clinicians is to identify a diagnostic marker indicative of a causal mechanism associated with fibromyalgia to increase the accuracy of diagnosis. Current research suggests that central sensitization is a primary candidate representative of the pathophysiology underlying fibromyalgia.^25,26 The current criteria were not constructed to be specific to people with central sensitization but rather individuals with a cluster of symptoms that expert panels of clinicians have defined as fibromyalgia. The criteria likely diagnose a consistent spectrum of patients; however, they may not capture the true presence of fibromyalgia. The specific mechanism responsible for the sensitization associated with fibromyalgia development should be elucidated since central sensitization has multiple etiologies (e.g. bacterial infection, inflammation, etc.).^27,28 This should allow for the separation of the overall population based upon the underlying mechanism into specific clinical groups each with a unique underlying pathology and a consistent set of symptoms. The following section presents findings on potential pathophysiological indicators of fibromyalgia.

Findings on pathophysiological perturbations in fibromyalgia

Research elucidating the pathophysiology of fibromyalgia provides some promising avenues for novel diagnostic markers. There is a growing body of evidence suggesting links between chronic pain and central sensitization, including lower pain thresholds and hyperalgesia.^25,26 Widespread hyperalgesia differentiates fibromyalgia from other states of central sensitization, however it does not yet have the capacity to differentiate it from other similarly presenting disorders with or without the presence of central sensitization, such as myofascial pain syndrome.^26,29

Several biological mechanisms have been implicated in the development of the sensitized state in fibromyalgia. Biomarkers associated with these mechanisms are shared between several disorders and can be used to develop cutoffs specific to fibromyalgia relative to other conditions. A comprehensive systematic search of Medline, Central (including Medline ePub Ahead of Print, In-Process, and Other Non-Indexed Citations), and EMBASE was conducted to determine the mechanisms that led to or are associated with the sensitized state in patients diagnosed with the current definition of fibromyalgia. The complete search strategy includes a comprehensive list of subject headings and text words to describe ‘fibromyalgia’ and various classes of biomarkers; this can be found in Appendix A. Studies assessing the presence of biomarkers (or lack thereof) in fibromyalgia typically used the 1990 criteria to diagnose their clinical population. The search indicated that hypothalamic pituitary axis (HPA) hormones, immune and inflammatory markers, neuropeptides and neurohormones, and advanced brain imaging were the most investigated diagnostic markers indicative of central sensitization and fibromyalgia. Here we present a brief summary of our literature search findings.

HPA hormone perturbations are present in fibromyalgia and other related disorders with suspected underlying central sensitization such as major depressive disorder, post-traumatic stress disorder (PTSD) or chronic fatigue syndrome. The combination of adrenocorticotropic releasing hormone (ACTH) and cortisol levels in fibromyalgia presents a distinct profile capable of differentiating it from other disorders. There is growing consensus in the literature that high ACTH levels suggest hyper responsiveness in pituitary release in response to corticotropin releasing hormone (CRH). This has been confirmed using exogenous infusions of CRH. Plasma or 24 h urinary cortisol levels are normal to low in people with fibromyalgia, indicating hyporesponsivenes at the adrenal glands to ACTH.^30–37 In depression and PTSD, cortisol levels are chronically elevated whereas in chronic fatigue syndrome cortisol and ACTH levels are normal.^37–40 Evening cortisol levels have been shown to be higher than normal in fibromyalgia and lower than normal in chronic fatigue syndrome.^39,41 These factors provide evidence of differences in HPA regulation between fibromyalgia and other central sensitization disorders.

Total oxidative status and immune responses are also high in fibromyalgia.⁴² The presence of antiserotonin antibodies is more common between fibromyalgia and chronic fatigue syndrome relative to other disorders.⁴³ Polymorphisms in genes coding for serotonin transporters and catechol-o-methyl transferase are associated with high pain sensitivity in fibromyalgia. These findings suggest there may be a neuroimmune basis to this disorder. A robust effect demonstrated in several studies suggests that levels of interleukin (IL)-6, IL-8 and IL-10 are high in fibromyalgia relative to healthy normal or other pain and central sensitivity disorders.^44–46 Furthermore, tumor necrosis factor α has been consistently elevated in disorders of central sensitization, including fibromyalgia.^45,47–49 Positive correlations exist between these inflammatory markers and clinical symptom severity. Zanette and colleagues⁵⁰ identified a strong correlation between increased serum brain-derived neurotrophic factor and S100B protein levels, which is associated with the coexistence of neurological disease and central sensitivity syndrome, with lower pressure pain thresholds in patients with fibromyalgia. Their findings provide a significant initial step towards developing biomarkers diagnostic of fibromyalgia, ultimately to create a well defined group and clinical definition.

Advanced brain imaging in fibromyalgia has demonstrated increases in functional connectivity between anatomical cortical regions associated with attention, emotion and somatosensory processing, including the anterior cingulate cortex, anterior prefrontal cortex, parietal cortex, dorsolateral prefrontal cortex and the insula.⁵¹ Increases in functional connectivity between these areas is associated with symptom (pain, depression) severity and pain duration in fibromyalgia.⁵² There have also been studies demonstrating attenuated blood flow to brain areas associated with inducing analgesic effects, and increased activity in the primary and secondary somatosensory cortices in people with fibromyalgia.⁵¹ This suggests that their nervous system is compensating for the increase in nociceptive signals received from the spinal cord and is being subject to hypermetabolic states due to large amounts of sustained afferent input. Increases in the glutamate to glutamine ratio are positively associated with the degree of functional connectivity and metabolism in brain areas implicated in central sensitization and fibromyalgia.^53,54 Decreases in dopamine binding and precursor uptake are also associated with the attentional and pain processing abnormalities observed in fibromyalgia.^55,56

These findings point to a multi axial interaction between neurological, endocrine and immune systems that results in the development of central sensitization in fibromyalgia. We suggest the development of new diagnostic criteria that are based upon clinical and central sensitization attributes that better characterize fibromyalgia. At present, the application of the diagnostic criteria will result in a heterogeneous group that consists of subgroups.

Discussion

Given these findings, researchers should strive towards creating subgroups within patients diagnosed by the current criteria or those with central sensitization, using some of the well researched biomarkers. This should identify distinct underlying pathophysiological mechanisms among the patients and create novel groups, one of which should be fibromyalgia. For example, biomarkers that are common to fibromyalgia and other disorders, such as cortisol, can be used to develop diagnostic cutoffs that help to create better boundaries for each condition and thus improve their distinct definitions. Biomarkers may also be used to understand whether fibromyalgia is truly a singular entity or a psychosomatic manifestation of a spectrum disorder continuous with other psychiatric and pain conditions such as depression, chronic fatigue syndrome or myofascial pain syndrome. A cluster analysis or discriminative function analysis may be used to create a set of criteria that diagnose a homogenous group representing fibromyalgia. Clinical signs and symptoms in combination with indicators of pathophysiological mechanisms known to be associated with fibromyalgia and overlapping disorders should be included. These analyses may inform which variables are highly predictive of overlapping disorders and whether there is a boundary that separates symptomatically overlapping conditions. Following this, the predictive ability of a biomarker profile that can differentiate fibromyalgia from other central sensitization disorders should be undertaken.

Ideally, selected biomarker panels should be able to diagnose fibromyalgia during its earlier phases, during a routine exam or in the presence of questionable symptoms.^57–59 The biomarker panel profile should indicate the stage or severity of the disorder, be responsive to clinical change and thereby allow for earlier intervention and prevention of progression. Ideally, the biomarker panel should also be responsive to the initiation, continuation, or cessation of external interventions as this will indicate the patient’s responsiveness to these interventions. This should address the limitation presented by the 2010 and subsequent criteria, whereby they measure the severity of a patient who already has fibromyalgia symptoms rather than to recognize the presence of the disorder at any of its stages.

In addition to these disease-specific attributes, the ideal biomarker should be acquired easily, noninvasively and affordably for efficient clinical application. Other easily measured and validated clinical features of central sensitization such as the ‘pinch and roll’ technique, pressure algometry, brush allodynia and weighted pinpricks that provide quantitative measures of pain pressure thresholds and expansion of the receptive fields should be investigated for their utility to diagnosing fibromyalgia.^2,60,61 Cold detection threshold as well as dermatographia can also be considered since they reflect the autonomic properties which seem to associated with the manifestation of fibromyalgia.^62,63 Finally, the current clinical criteria should be revisited upon the development of an accurate marker that reflects the pathophysiology underlying fibromyalgia. Validation of the criteria or a subset of the criteria that accurately capture the newly defined fibromyalgia population should be conducted, and they should also be used to augment and indicate the clinical presence of fibromyalgia.

Conclusion

A problem underlying the diagnosis and management of fibromyalgia, extending to other chronic pain disorders, is the symptom-specific rather than a mechanistic approach taken towards its diagnosis and treatment.⁶⁴ This method of diagnosis results in the presence of different clinical subgroups presenting different pathophysiological mechanisms under a single pain disorder diagnosis, as is present in fibromyalgia. Many patients may be receiving treatments that may not be suitable for their presenting condition. There is a need for well defined mechanism-based criteria to describe the specific characteristics of fibromyalgia. This should guide the development of more accurate diagnostic methods and effective treatments.

Footnotes

Appendix A

Database: Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present>

Search Strategy:

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Database: EBM Reviews - Cochrane Central Register of Controlled Trials <February 2017>

Search Strategy:

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Author’s Note

Dinesh Kumbhare and Sara Ahmed are First Co-Authors of the article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

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A narrative review on the difficulties associated with fibromyalgia diagnosis

Abstract

Keywords

Introduction

Methodological problems associated with the accepted classification and diagnostic criteria

Findings on pathophysiological perturbations in fibromyalgia

Discussion

Conclusion

Footnotes

Appendix A

Author’s Note

Funding

Conflict of interest statement

References