Unravelling Fibromyalgia in Psoriatic Arthritis

Abstract

Fibromyalgia is a common condition causing widespread pain, fatigue, sleep disturbance, and cognitive dysfunction. It frequently coexists with chronic rheumatic diseases, including psoriatic arthritis (PsA), complicating diagnosis and management. This narrative review explores the interaction between fibromyalgia and PsA, highlighting recent studies that demonstrate that between 18% and 64% of patients with PsA have fibromyalgia with significant impact on disease assessment and quality of life. Patients with fibromyalgia have markedly higher scores for pain, tenderness, fatigue, poor sleep, and standard PsA disease activity measures. Where this overlap occurs “disease activity” indices often reflect fibromyalgia symptoms rather than true inflammation, leading to potential overtreatment with disease-modifying drugs rather than appropriate pain-modulating or lifestyle interventions. Additionally, fibromyalgia symptoms exist along a continuum, with many patients showing subthreshold manifestations that still affect function and well-being. Tools such as the Fibromyalgia Impact Questionnaire and Polysymptomatic Distress Scale help distinguish the central sensitization symptoms that characterize fibromyalgia from inflammatory activity and damage in joints and tendon sheaths that characterize PsA. Both peripheral and central pain-related neural mechanisms, including comorbid factors such as obesity and disease burden, contribute to fibromyalgia in PsA. Activation of the stress response likely contributes significantly to fibromyalgia in this setting. Fibromyalgia itself is seen not simply as a comorbidity but as part of the body’s neurobiological stress response to chronic illness. Recognizing fibromyalgia within PsA is crucial to tailor management, improve outcomes, and avoid unnecessary treatments. This complex clinical picture requires nuanced management beyond that of inflammation alone.

Key Summary Points

Fibromyalgia commonly coexists with psoriatic arthritis, and overlapping clinical features of the two conditions can impact clinical assessment and management.

Both peripheral and central pain-related mechanisms, including influence of comorbid factors such as obesity and psoriatic disease burden, contribute to fibromyalgia in psoriatic arthritis through impact on neural sensitization mechanisms.

Composite disease activity tools utilized in psoriatic arthritis include various patient-reported measures which can be influenced by the coexistence of fibromyalgia, impacting their reliability.

Concomitant fibromyalgia is associated with worse disease outcomes in fibromyalgia, including failure to achieve low disease activity state and poorer response to therapy.

Introduction

Psoriatic arthritis (PsA) is a common inflammatory and potentially destructive condition variably targeting entheseal regions, tendon sheaths, and joints in identifiable patterns [1]. PsA interacts with a wide range of comorbidities which collectively contribute to the overall health burden of the patient [1]. Fibromyalgia commonly accompanies PsA. Through its compilation of independent and characteristic symptoms of pain, fatigue, sleep disturbance, cognitive dysfunction, and hypersensitivity in many neural systems, fibromyalgia will influence clinical presentation, assessment, management, and outcomes of PsA [2].

This narrative review explores the prevalence of fibromyalgia in PsA, examines potential risk factors and mechanisms involved in fibromyalgia in this setting, and discusses the challenges of diagnosis and consequences of the co-occurrence of fibromyalgia and PsA. A focus on neural sensitization mechanisms is incorporated.

Prevalence of Fibromyalgia in Patients with Psoriatic Arthritis

Fibromyalgia is a common comorbidity in patients with PsA, with pooled prevalence of 18% in systematic review data, although rates range from 18% to 64% between studies [3]. An increased rate of fibromyalgia, when compared to the general population, is not unique to PsA, and is demonstrated in other inflammatory arthropathies. Estimated global prevalence of fibromyalgia in the general population is 2–4%, with highest rates particularly in middle-aged women [4]. In rheumatoid arthritis (RA), estimated pooled prevalence is 21%, again with considerable variability of 5–52% between studies [3]. In axial spondyloarthritis, the prevalence of comorbid fibromyalgia ranges from 4% to 25%, with similar pooled prevalence of approximately 15% when separated into those meeting definitions for ankylosing spondylitis, axial spondyloarthritis (AxSpA), or non-radiographic axial spondyloarthritis (nrAxSpA) [3]. The consistent finding of higher rates of fibromyalgia compared to the general population suggests that chronic inflammatory arthritis influences fibromyalgia pathogenesis.

Several methodological factors account for the variability of data, particularly significant heterogeneity between study cohorts and differences in study definition of fibromyalgia. The American College of Rheumatology (ACR) classification criteria are most frequently used to define fibromyalgia in clinical studies; however, various versions exist. The 2010/2011 criteria removed the tender point examination necessitated by the original 1990 criteria, instead including the widespread pain index (WPI) and symptom severity score (SSS) to acknowledge the importance of somatic symptoms beyond pain [5, 6]. This was further modified in 2016 to include a modified widespread criterion alongside emphasizing that a diagnosis of fibromyalgia is valid irrespective of other diagnoses, and that the self-reported version of the criteria are valid for research studies but not clinical diagnosis [7]. Population-based data comparing the ACR criteria in the general population demonstrates higher prevalence with the 2016 criteria (5.4% versus 1.7% and 1.2% respectively for the 1990 and 2010/2011 criteria), suggesting more self-reported symptom-based tools may identify more patients with possible fibromyalgia [8]. This is consistent with studies of fibromyalgia in RA, with higher prevalence of fibromyalgia defined using the 2010/2011 criteria compared to the 1990 criteria [9]. In PsA, however, heterogeneity was not improved when stratified by classification criteria, although greater consistency was seen among studies using the 2010/2011 criteria [9]. Of note, the ACR fibromyalgia classification criteria have not been validated for use in patients with concurrent inflammatory arthritis and should be interpreted with care [9].

Comparison of epidemiological data is further challenged by use of definitions outside of the ACR criteria in some PsA cohorts. Widespread pain, as defined by the WPI alone, is one such example, noting 20.6% of patients with PsA fulfilled this diagnosis in a recent study, compared to 11.1% meeting 2016 ACR criteria [10]. Alternatively, some studies use short screening instruments such as the Fibromyalgia Rapid Screening Tool to define fibromyalgia [11]. Regardless of criteria, the diagnosis of fibromyalgia is defined as either present or absent, potentially overlooking the spectrum of fibromyalgia and the possibility of sub-criteria symptoms that may influence a patient’s reporting of pain, fatigue, and function and impact psoriatic disease activity scores [2].

Potential Mechanisms Linking PsA and Fibromyalgia

Central Sensitization and PsA and Fibromyalgia

While PsA is a chronic inflammatory disease targeting entheseal and synovial tissues in different regions of the body [1], fibromyalgia is a disorder of pain-related neural hypersensitivity resulting in widespread body pain and tenderness [12]. What pathophysiological mechanisms might link PsA with fibromyalgia?

Central sensitization is a term used to describe the process by which the nervous system becomes hyper-responsive to both mechanical and nociceptive pain-related stimuli, as occurs in fibromyalgia [13]. This process occurs in the brain and spinal cord and may be initiated or modulated by both peripheral and/or central neurophysiological events. The resulting pain type is defined mechanistically as nociplastic pain [14].

Peripheral Inputs

Peripheral nociceptive inputs travelling in small, myelinated A-delta fibers or non-myelinated C-fibers transmit information from joints, tendon sheaths, or entheses to secondary pain transmission neurones in the outer regions of the spinal dorsal horn and then onto the brain for further processing. Joint inflammation is a potent stimulus of this characteristic pain pathway. Such pain is well localized to the source of nociception.

However, intense and persistent inflammation will lead to change in function of these pain-related transmission neurones. They become increasingly more responsive to lower levels of nociceptive input, a phenomenon called central sensitization [15].

Additionally, the joint, tendon, and entheseal nociceptive fibers also connect to the deeply placed wide-dynamic range dorsal horn neurones that have other important roles in central sensitization. Depending on the intensity of the stimuli the “bottom-up” neural inputs to these dorsal horn neurones may facilitate significant (central) sensitization of these neurones [16]. This means that these multi-input pain-related neurones will then respond to other non-nociceptive inputs, such as those associated with large, myelinated mechanoreceptors, for example the A-beta low threshold mechanoreceptor fibers, which transmit information related to touch, movement, and position. These inputs interact with the nociceptor-related pain pathways and allow for translation of these otherwise innocuous mechanical stimuli into pain [15, 17, 18].

The pain resulting from this process reflects the large peripheral fields of the mechanoreceptors and is therefore more regionalized and widespread, rather than localized to a specific joint [12]. Importantly, these deeper neurones have significant modulation by downward pathways from the brain stem and brain, such that the sensitivity can be amplified or muted [19].

Nociception from different types of chronic inflammatory and degenerative arthritis has been implicated as a potential mechanism in contributing to central sensitization and fibromyalgia [20, 21]. This process likely also occurs in PsA. It is noted that persistent inflammation in PsA may be obvious clinically or may be more subtle where indicative patient inflammatory symptoms may only be clarified through imaging and other investigation techniques [22]. Thus, subclinical inflammation may contribute to patients experiencing more widespread pain than is clinically evident. It is not clear, however, if multi-joint inflammation in PsA by itself, whether overt or covert, can prime the spinal dorsal horn and hence the central nervous system to cause central sensitization to a degree that would result in the widespread pain and tenderness that characterizes fibromyalgia.

Fibromyalgia has an increased prevalence of up to 10 times the general population background rate in all studied chronic inflammatory diseases [3, 14]. Is there something different about the inflammation mechanisms of PsA compared to other chronic inflammatory joint diseases that might particularly contribute to the fibromyalgia process? Persistent inflammation in PsA is associated with elevated levels of pro-inflammatory cytokines, which can interact with normal pain modulation pathways and promote neural changes that facilitate increased pain perception. Important cytokines contributing to peripheral inflammation in PsA include tumor necrosis factor (TNF) alpha, interleukin (IL)-17, and IL-23. Clinical use of agents that block these cytokines all reduce levels of pain in PsA [23].

However, as stated above, the rates of fibromyalgia in PsA are like those in RA, systemic lupus erythematosus (SLE), AxSpA, and other chronic inflammatory joint diseases where different sets of cytokines contribute to the pathophysiology [24, 25]. There is little current evidence to indicate that the PsA cytokine signature is more likely to cause fibromyalgia than the cytokine mix that is present in RA, SLE, AxSpA, or other inflammatory joint diseases [26]. Additionally, chronic inflammatory diseases affecting other non-synovial/entheseal organ systems have different cytokine and inflammatory signatures, but all have increased rates of fibromyalgia [24].

Central Inputs

Importantly, fibromyalgia in the community is usually present in populations of patients who do not have chronic inflammatory joint diseases or other specific peripheral conditions which cause nociceptor activation [12]. The more common mechanism causing central sensitization is derived from stress-related neurobiological mechanisms within the brain and spinal cord which modulate the pain-related neural pathways independent of abnormal peripheral sensory input [27]. These “top-down” mechanisms are also present in patients with PsA. Figure 1 summarizes these pathways.

Fig. 1.

Central sensitization is the key neurophysiological pain mechanism in fibromyalgia. Peripheral nociceptive inputs from the inflamed psoriatic-associated joint or enthesis will activate dorsal horn pain-related neural pathways and potentially contribute to increased neurone sensitivity to other sensory inputs. These include mechanoreceptor inputs which result in regionalized pain. Descending pathways from the brain related to the stress response also have powerful effects on these and other similarly located neurones elsewhere in the spinal cord allowing otherwise innocuous mechanoreceptor input to contribute to more widespread pain. Figure created with BioRender.com

The stress response is not an “all or none” response but rather reflects a gradient of brain output responses which encompass the hypothalamic pituitary axis, the sympathetic nervous system, and brain-related neural circuits, including those that modulate spinal cord dorsal horn pain transmission neuron sensitivity [27, 28]. Each of these components, in different ways in different patients, can facilitate the central sensitization process behind fibromyalgia [27, 29].

A variety of psychosocial stressors are associated with fibromyalgia [30]. Sleep disturbance, fatigue, and cognitive dysfunction are common associates of the widespread pain that characterizes fibromyalgia and these symptoms contribute to many of the classification and diagnostic criteria for fibromyalgia [7]. In the context of PsA, painful joints, tendons, and other tissues may contribute to sleep disturbance which could modify central processes that modulate dorsal horn neuronal sensitivity and thus act as a trigger for development of fibromyalgia [13, 27].

Psychosocial factors, present in any chronic disease, also contribute to central mechanisms feeding into the fibromyalgia mechanism [29, 31]. Factors such as loss of income, effects on family relations, monetary consequences of modified work, and uncertainty about the future of the condition, the requirement for medical and allied health input, medication demands and potential side effects, frequent pathology tests, and the like, all contribute to a heightened background of psychosocial distress [1, 23]. These everyday factors that can activate the stress response associated with fibromyalgia are summarised in Table 1 [31, 32].

Table 1.

Selected stress-related factors in psoriatic arthritis influencing neurobiological responses in fibromyalgia

Factors increasing neural sensitization in fibromyalgia

Genetic factors modifying neural sensitivity

Early life physical and or emotional experiences

Background emotional distress

Burden of disease  Stigma and discrimination  Pain, stiffness, sleep disturbance, fatigue  General effect on health—unfit, overweight, depression  Need for tests, medical review, treatments, drugs  Loss of quality of life  Modification of social and work roles

Psychological response to the above—anxiety, depression, anger

Additionally, psoriasis alone is associated with a high impact on a patient’s quality of life and general well-being [33] and likely contributes to background emotional distress that is a driver of fibromyalgia [23]. In an online survey of 4978 persons with psoriasis from 20 countries, with 30% reporting concomitant PsA, 48% reported that their disease had a very large to extremely large effect on quality of life [34]. Most patients had experienced stigma and discrimination (82%) and negative effect on relationships (81%) in their lives, and 58% were not involved in deciding their treatment goals.

In relation to PsA in particular, it has been noted that psychological health is a contributor to PsA activity and outcomes that needs careful management [35].

Patients with PsA may have elevated body mass index (BMI) or be obese. As discussed later, the pro-inflammatory cytokines in visceral fat may in turn contribute to the neural sensitization driving fibromyalgia [23].

Risk Factors for Fibromyalgia in Patients with PsA

The risk factors for the development of fibromyalgia in an individual are various. Genetic influences account for up to 50% of the likelihood of fibromyalgia occurrence in any one individual [36]. Similarly, early life adversity, environmental triggers, psychosocial and physical stressors, and lifestyle factors such as very low physical activity levels, smoking, and alcohol intake are all recognized elements increasing the chance of fibromyalgia development [37–40]. Characteristics that are associated with higher prevalence of fibromyalgia in the general population also increase the likelihood that patients with PsA will experience abnormal pain processing or concurrent fibromyalgia. Fibromyalgia is approximately twice as common in women in general, and female patients with PsA are up to three times more likely to have coexisting fibromyalgia than men [10, 41, 42].

Active inflammation heightens physiological stress in patients with inflammatory arthritis, resulting in a more permissive environment for the development of nociplastic pain and increased central sensitivity [15]. In a cross-sectional analysis of over 1800 patients with psoriatic arthritis from the CorEvitas registry, patients with PsA and fibromyalgia were also more likely to have a more recent arthritis diagnosis and have higher objective measures of active arthritis and inflammatory load [10]. The risk of development of concomitant fibromyalgia is seen to be highest within the first 12 months after inflammatory arthritis diagnosis, when inflammation is less likely to have been controlled [43]. Other increased physical stressors associated with the likelihood of concurrent fibromyalgia include the number of physical comorbid conditions [10]. This is an identified risk factor for the presence of fibromyalgia in the general population as well as in patients with PsA [10, 44]. Elevation in BMI is found in up to 45% of patients with PsA and results in higher mechanical load on joints, entheses, and related structures [45]. The low-grade persistent systemic inflammatory state occurring with obesity may also promote triggering and maintenance of increased central sensitivity and higher fibromyalgia risk in these patients [10, 46, 47].

Psychological stressors can contribute to the development of abnormal pain processing and increased central sensitivity [38, 39]. Poor mental health has been identified as a significant predictive factor for the development of fibromyalgia in patients with inflammatory arthritis [43, 48]. Patients with PsA reporting worse current levels of depression and anxiety, and lack of full employment were more likely to have concurrent fibromyalgia in the large CorEvitas registry study, although the influence of these factors and the presence of fibromyalgia can be bidirectional [10].

Challenges of Diagnosing Patients with Fibromyalgia and PsA

The coexistence of fibromyalgia and PsA presents various challenges, with important implications for assessment, treatment, and research. Fibromyalgia and PsA share overlapping clinical features, including pain, stiffness, and fatigue (Fig. 2), which can make distinguishing whether symptoms are driven by peripheral inflammation or central sensitization difficult, leading to ambiguity during both diagnosis and assessment of disease activity [22, 49, 50]. Shared associations with comorbidities such as depression, obesity, and osteoarthritis further entangle these two conditions [51, 52]. PsA itself is a heterogenous disease with varied clinical features and can, at times, be challenging to diagnose [53]. Whilst there are no available biomarkers to aid in the diagnosis of fibromyalgia, the same can be said of PsA, with no disease-specific autoantibodies and elevated acute-phase reactants in only approximately half of patients [54].

Fig. 2.

The overlap of clinical features in psoriatic arthritis and fibromyalgia. CRP C-reactive protein, ESR erythrocyte sedimentation rate, IBD inflammatory bowel disease, QoL quality of life, IBS irritable bowel syndrome

The variability of tissues involved in PsA and the limitations of evaluating enthesitis create unique challenges in distinguishing between inflammatory and non-inflammatory mechanisms in PsA compared to RA [52, 55]. Enthesitis is a hallmark of PsA, seen in at least 35% of patients [56]. It is conventionally assessed by clinical examination of entheseal point tenderness; however, this lacks specificity, with many entheses being in close proximity to accepted fibromyalgia tender points and may be influenced by allodynia [57]. As a result of poor vascularity, enthesitis may lack visible signs of inflammation [9]. Enthesitis assessed by tenderness is overestimated in patients with PsA and comorbid fibromyalgia [58]. Imaging modalities, particularly ultrasound, demonstrate better sensitivity and specificity than physical examination for the detection of enthesitis [57]. In patients with PsA and fibromyalgia, ultrasound potentially aids disease activity assessment more than composite clinical scores, with consistent ultrasound findings in those with and without comorbid fibromyalgia, compared to significant increases in clinical composite scores [59]. Other objective markers of disease activity, such as joint swelling, erosive disease and radiographic progression are less prevalent in PsA compared to RA [60, 61]. Addition of imaging modalities to assess disease activity in PsA is not without its own shortcomings, again in comparison to RA, due to the complexity of assessing for peritendinitis, periostitis, and osteitis alongside enthesitis, synovitis, tenosynovitis, and erosive disease [52].

Alongside measures of tenderness, comorbid fibromyalgia influences patient-reported components of composite disease scores in PsA. Patients with PsA and fibromyalgia score significantly higher on various PsA disease activity tools, including the Disease Activity in Psoriatic Arthritis (DAPSA), Composite Psoriatic Disease Index (CPDAI), Leeds Enthesitis Index (LEI), and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [41, 49, 62–64]. These composite indices include subjective patient-reported outcomes, which contribute significantly to the overall score [41]. Patients with fibromyalgia report high levels of pain, tenderness, fatigue, functional impairment, and lower quality of life, leading to disproportionally high composite scores [10]. Notably, one study found that no patient with PsA and fibromyalgia was able to achieve minimal disease activity, compared to 43% of patients without comorbid fibromyalgia [41]. Conversely, more objective measures such as C-reactive protein (CRP), swollen joint count, or skin psoriasis tend not to be influenced by the presence of absence of fibromyalgia, although a degree of association between objective measures of inflammation and fibromyalgia may be seen in some studies [10, 42, 64]. This highlights the limitations of disease activity scores in differentiating inflammatory from non-inflammatory pain.

Given these challenges, a need for thorough evaluation is required at the time of diagnosis and assessment of disease activity and treatment effect. In clinical practice, integration of screening for fibromyalgia in patients with PsA, careful interpretation of subjective outcome measures and incorporation of objective imaging tools are prudent to distinguish between inflammatory and non-inflammatory drivers of symptoms and avoid unnecessary changes to immunological therapy, particularly in those with difficult to treat disease [52]. Likewise, clear documentation of fibromyalgia status in cohort studies and clinical trials utilizing validated diagnostic tools is essential [10].

Consequences of Fibromyalgia in Patients with PsA

There are significant consequences for patients with PsA who concurrently experience fibromyalgia. Coexisting fibromyalgia is associated almost uniformly with higher PsA scores when measured with instruments incorporating tender joint counts, pain, and patient-reported outcomes, including DAPSA, CPADI, Health Assessment Questionnaire (HAQ), and BASDAI [41, 48, 49, 63, 65]. The challenges of distinguishing between enthesitis and fibromyalgia during clinical assessment may result in possible misclassification of treatment-resistant PsA [9, 22]. Patients with fibromyalgia also report higher levels of fatigue, more anxiety and depression, worse sleep quality, and poorer quality of life [48, 49, 63]. There is a positive correlation between fibromyalgia severity scales and PsA disease activity measures [42]. These differences are reduced or even eliminated when using more objective measures such as CRP, swollen joint or dactylitis counts, physician assessment, or imaging such as ultrasound [22, 41, 47, 65]. Fibromyalgia can combine with other non-inflammatory mechanisms such as post-inflammatory joint damage and biomechanical factors in contributing to persistent symptoms of difficult-to-treat PsA [52].

Concomitant fibromyalgia is associated with failure to achieve a low disease activity state in patients with PsA [41, 66]. It has also been linked to poorer response to therapy. In patients with inflammatory arthritis treated with 6 months of TNF inhibitor therapy, those who failed to respond to therapy were found to have impaired central descending pain modulation, an indicator of central sensitization-associated pain [67]. Patients with PsA and concurrent fibromyalgia in a large US cross-sectional cohort study were more likely to have used three or more biologic or targeted synthetic disease-modifying antirheumatic drugs and be using non-steroidal anti-inflammatory drugs, narcotics, and other analgesics [10]. In another investigation of patients with PsA using biologic therapy, after 1 year, those without fibromyalgia at baseline were 12 times more likely to achieve remission using a definition that included tender joint count and enthesitis [66], suggesting that response to therapy in individuals, however, may be influenced by the measurement tools used. Poor therapeutic responses may impact on patient satisfaction with therapy, and adherence to treatment as has been found in rheumatoid arthritis [68].

Obesity and metabolic syndrome are frequently found in patients with PsA and can contribute to increased central sensitivity [45, 69, 70]. In patients with PsA and these comorbidities, there is more joint pain, higher disease activity, and poorer response to anti-TNF and other therapies [46, 47, 71, 72]. Although metabolic syndrome is associated with higher PsA disease activity, it is not associated with higher levels of PsA-related radiographic damage [73].

These associated consequences may result in increased healthcare utilization by patients with PsA and concurrent fibromyalgia, and subsequent increased economic burden both for the patient and society [74].

Conclusion

Fibromyalgia occurs more commonly in chronic inflammatory arthropathies; however, untangling overlapping clinical features in patients with both fibromyalgia and PsA presents unique challenges for the clinician and researcher. Recognizing the influence of fibromyalgia on PsA, particularly with those with difficult to treat disease, is essential to permit accurate assessment of inflammatory disease and guide treatment decisions.

Author Contributions

All authors contributed equally to the final paper. Kate E Findeisen, Emma K Guymer and Geoffrey O Littlejohn all wrote, appraised and edited all sections. All authors read and approved the final version of the manuscript.

Funding

No funding or sponsorship was received for the publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Kate E Findeisen, Emma K Guymer and Geoffrey O Littlejohn have no conflicts of interest to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.