Increased risk of fibromyalgia in patients with atopic dermatitis: A nationwide longitudinal study

Introduction

Fibromyalgia, previously referred to as fibrositis syndrome, was thought to involve significant peripheral inflammation as a key component of its pathology.¹ Fibromyalgia is a condition characterised by chronic widespread pain and symptoms such as hyperalgesia and allodynia. Commonly reported issues include fatigue, sleep disturbances, mood disorders, and reduced quality of life.^2-4 Other symptoms include restless legs syndrome, chronic headaches, stiffness, leg cramps, dysesthesias, dizziness, vertigo, and hypersensitivity to environmental factors such as noise, light, and temperature. Irritable bowel and bladder symptoms, temporomandibular joint syndrome, and post-exertional exhaustion are also frequently noted.^5-8 The etiopathogenesis of fibromyalgia is considered multifactorial, involving genetics, central sensitisation, impaired pain control, hormonal dysregulation, infections, trauma, psychological stress, neuroinflammation, and nutritional factors.^9-11

Atopic dermatitis (AD) is the most common chronic inflammatory skin disorder. Evidence suggests that its development is influenced by genetic factors, skin barrier dysfunction, and immune dysregulation.^12,13 A compromised skin barrier exacerbates skin inflammation. Type 2 cytokines, along with interleukin-17 and interleukin-22, play a key role in skin barrier dysfunction and the progression of AD.¹⁴ Recent insights into the pathophysiology of AD have highlighted the significance of epidermal lipid profiles, neuroimmune interactions, and microbial dysbiosis.¹⁵ Understanding these factors is essential for developing targeted therapeutic strategies aimed at improving skin barrier function and modulating immune responses in AD patients.

Although AD and fibromyalgia are both associated with chronic inflammation, the exact relationship between these two conditions remains unclear. This study aims to investigate the relationship between AD and fibromyalgia, focusing on whether AD increases the risk of developing fibromyalgia later in life. Given the shared chronic inflammatory nature of these conditions, we hypothesise that patients with AD, particularly those with varying levels of disease severity and age, are at an elevated risk of fibromyalgia.

Methods

Inclusion criteria for patients with atopic dermatitis and matched controls

Adolescents aged between 10 and 19 years and adults aged ≥ 20 years who were diagnosed with AD (ICD-9-CM code: 691.8) by board-certified dermatologists and rheumatologists based on skin tests between January 1, 1998, and December 31, 2013, and who had no fibromyalgia history before their AD diagnosis were included in the AD cohort [Figure 1]. Exact matching was used to match this cohort in a 1:10 fashion to controls without diagnoses of either fibromyalgia or AD and related diseases (ICD-9-CM code: 691) prior to enrolment for other medical causes on the basis of age (± 1 year), sex, enrolment time, other atopic diseases (asthma, allergic rhinitis, allergic conjunctivitis), income level (levels 1-3 per month: ≤15,840 New Taiwanese Dollars- NTD), 15,841-25,000 NTD, and ≥25,000 NTD), and urbanisation level of residence (levels 1-5, most to least urbanised), a proxy for healthcare availability in Taiwan.¹⁹ Additionally, Charlson Comorbidity Index (CCI) and all-cause clinical visits (the number of clinical visits per year) were provided for the AD and the matched-control cohorts. CCI, comprising 22 physical conditions, was also assessed to determine the systemic health conditions of all enrolled subjects.²⁰ All-cause clinical visits for both cohorts were included as a variable to account for potential detection bias. Diagnosis of fibromyalgia (ICD-9-CM code: 729.1) was documented at least twice by board-certified rheumatologists, pain specialists, or psychiatrists during the follow-up period (from enrolment to December 31, 2013, or death). Disease severity was defined based on treatment modalities recorded in the claims database. Patients who received only topical therapy were classified as having mild AD, while those requiring systemic treatments for more than 3 months, such as steroids, cyclosporine, azathioprine, methotrexate, or mycophenolic acid, were classified as having moderate-to-severe AD.

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Figure 1:

Study flowchart.

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Results

The demographic and clinical features of the AD cohort and the control group have been presented in Table 1. There were 4147 patients with AD, and 41,470 age- and sex-matched controls in this study. The mean age was 27.01 ± 16.63 years in the AD group and 26.98 ± 16.67 years in the group without AD. In the AD group, 55.2% were females. There were 84.4% of AD cases in the mild disease severity, and 15.6% of patients in the moderate to severe disease severity. The comorbidities with other atopic diseases included asthma (24.9%), allergic rhinitis (54.1%), and allergic conjunctivitis (32.6%). The patients with AD tended to have higher CCI scores, more clinical visits, and lower income-related insured amount than the control cohort. However, the incidence of AD was polarised in urban and rural areas. The mean age of fibromyalgia diagnosis was 41.5 in the AD cohort and 54.3 in the control group. Furthermore, the mean duration between enrolment and fibromyalgia diagnosis was 4.4 years in the AD group and 6.5 years in the control cohort.

Table 2 presents the Cox regression analysis of the patients with AD and the risk of developing fibromyalgia. After adjusting for age, CCI score, and all-cause clinical visits, showed that patients with AD were associated with an increased risk (HR 7.12, 95% CI 5.37-9.43) of fibromyalgia. Stratified by age, the group younger than 20 years had the highest risk (HR 13.59, 95% CI 6.85-26.97), followed by those between 20 and 59 years (HR 6.31, 95% CI 4.4-9.03), and the risk was lowest in patients above 60 years (HR 3.89, 95% CI 1.64-9.19). The risk of developing fibromyalgia increased with the severity of atopic dermatitis compared to the control group. As per Table 3, 0.3% of the control group, 3.8% of the mild AD group, and 7.4% of the moderate to severe AD group had fibromyalgia. The adjusted HR of the mild AD group was 6.97 (95% CI 5.1-9.53), and the adjusted HR of the moderate to severe AD group was 7.72 (95% CI 4.18-14.27). As shown in Table 4, sensitivity analysis demonstrated that patients with AD had an increased risk of developing fibromyalgia after excluding the 3-year (HR 6.93, 95% CI 5.05–9.50) and 5-year (HR 5.49, 95% CI 3.83–7.87) observation period. Besides, the sensitivity analysis revealed that patients with AD had an increased risk of developing fibromyalgia, excluding enrolments after January 1, 2000 (HR 7.13, 95% CI 5.35–9.51), and also after January 1, 2003 (HR 7.13, 95% CI 5.35–9.51). The cumulative hazard curve of AD patients and the control group, each developing fibromyalgia, is shown in Figure 2.

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Figure 2:

Cumulative hazard curve of developing fibromyalgia among patients with atopic dermatitis and the control group.

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Discussion

The results of the study support a strong epidemiological association between AD and fibromyalgia. Patients with AD exhibited a significantly elevated risk of fibromyalgia, with an adjusted hazard ratio of 7.12 and a 95% confidence interval of 5.37 to 9.43, and this association remained consistent across disease severity, with hazard ratios of 6.97 for mild AD and 7.72 for moderate-to-severe AD. Early-onset AD appeared to confer the greatest risk, as patients under 20 years showed a hazard ratio of 13.59, suggesting heightened neuroimmune vulnerability. Building upon these epidemiological observations, it is essential to consider how neuroimmune dysfunction may serve as a common mechanistic link between AD and fibromyalgia.

Both AD and fibromyalgia are increasingly recognised as chronic inflammatory diseases with substantial neuroimmune involvement. In fibromyalgia, neurogenic inflammation may disrupt the communication between the innate immune system and both the peripheral and central nervous systems, contributing to central sensitisation.¹ Evidence suggests that immune activation alters nociceptive pathway sensitivity, as demonstrated by elevated pro-inflammatory mediators and the presence of both organ-specific and nonspecific autoantibodies in patients with fibromyalgia.²¹ For example, individuals with fibromyalgia often present with thyroid autoantibodies, most notably anti-thyroid peroxidase (TPOAb), which is more prevalent than anti-thyroglobulin (TgAb).²² The interplay between the immune and nervous systems in pain modulation has been increasingly recognised.²³ Studies have shown elevated epidermal mast cell concentrations in fibromyalgia patients, suggesting their role in neurogenic activation processes.¹

Neuroendocrine processes are triggered in response to stimuli, leading to increased vascular permeability and vasodilation. This activation engages key mediators of innate immunity, such as mast cells and dendritic cells, alongside T-lymphocytes, the central players in adaptive immunity.^24,25 Neuropeptides such as glutamate, substance P, calcitonin gene-related peptide, neurokinin A, nerve growth factor (NGF), and brain-derived neurotrophic factor are released.²⁶ Mast cells further contribute by secreting bradykinin, histamine, serotonin, and tumour necrosis factor (TNF), while T-lymphocytes release a range of cytokines and interleukins. Collectively, these processes define the complex phenomenon of neuroinflammation.¹¹ Stress and other psychological factors trigger neural responses that amplify pain perception. This can manifest as either classic mechanical nociceptive pain or neurogenic pain.²⁷ Similarly, certain symptoms and physical examination findings in patients with fibromyalgia point to the involvement of peripheral mechanisms. These include peripheral swelling, reticular skin discoloration, dermatographia, cutaneous dysesthesia, and even Raynaud’s phenomenon.¹ The heightened activation of abnormal mechanisms, including trauma, psychological factors, and emotional stress, contributes to the progression of fibromyalgia.¹¹

Mast cells function as primary immune effectors in AD, along with Th2 cytokines (e.g., IL-4, IL-6, IL-13), initiating the immune cascade by triggering IgE production through B cell class-switch recombination. This activation leads to sequential release of pro-inflammatory mediators, including Th1 cytokines (e.g., IL-2, IL-3, TNF-α) and chemokines.²⁸ During atopic reactions, excessive secretion of pro-inflammatory cytokines can cross the blood-brain barrier and activate neuroimmune mechanisms. These processes involve specific neural circuits, such as the anterior cingulate gyrus and insula, which play a role in behavioural modulation.^29,30 Thus, both AD and fibromyalgia exhibit overlapping neuroinflammatory mechanisms.

Fibromyalgia shows a distinct gene expression pattern marked by both Th-17 and Type I interferon activity, suggesting a possible autoimmune link in its development. Increased circulating IL-17 encourages T helper cells to produce cytokines like IL-6, IL-21, IL-23, and TGF-β, which, in turn, facilitate the growth, persistence, and function of Th17 cells in the condition.³¹ Similarly, the most significant risk factor for developing AD is a family history of atopic conditions, particularly AD.³² Genetic variations in immune pathway genes have been linked to a higher susceptibility to AD. Genome-wide studies have identified Th2 cytokines, such as KIF3A, IL-4, and IL-13, as key molecules in the development of AD.³³ Increased levels of IL-4 and IL-13 suppress filaggrin protein expression, resulting in skin barrier dysfunction.¹⁵ Additionally, functional polymorphisms in type 2 cytokine receptors (IL-4R and IL-13R) have been implicated in the pathogenesis of AD.¹⁵ Several other immune-related genes also play a role in AD development, including IL-31, IL-33, the signal transducer and activator of transcription 6, thymic stromal lymphopoietin (TSLP) and its receptors (IL-7R and TSLPR), interferon regulatory factor 2, Toll-like receptor 2, and the high-affinity IgE receptor α gene in certain populations.¹⁵ In summary, polymorphisms in genes related to T-helper cells, Toll-like receptors (TLRs), and interferon signalling influence the immune pathways underlying both AD and fibromyalgia.

Vitamin D deficiency has emerged as a significant focus in pain research, given its essential roles in bone metabolism, neural function, and muscular health.³⁴ Additionally, parathyroid dysfunction has been linked to fibromyalgia, potentially mediated by sympathetic hyperactivity and progesterone activity, both of which are involved in these conditions. The role of progesterone may also help explain why fibromyalgia is more prevalent in women.³⁵ However, clinical data assessing the relationship between blood vitamin D levels and symptom severity remains inconclusive.¹¹ Recent studies have identified associations between vitamin D receptor polymorphisms, cytochrome P450 family 27 subfamily A member 1 (CYP27A1) variants, and AD. CYP27A1 is known to influence vitamin D3 metabolism, which plays a key role in immune regulation.¹⁵ Therefore, vitamin D dysregulation may serve as a potential link between AD and fibromyalgia.

Limitation

This study has several limitations. First, the incidence of fibromyalgia may be underestimated, as only individuals who sought medical attention were included. This could lead to challenges in identifying all affected individuals. However, since our study participants were diagnosed by board-certified physicians rather than relying on self-reported questionnaires, the diagnostic validity is relatively higher. Second, due to the limitations of the NHIRD, fibromyalgia cases could only be identified using the ICD-9-CM code 729.1, with no access to further details such as syndrome severity or specific clinical features. Third, the NHIRD dataset lacks important information on factors such as food allergies, family history, personal lifestyle, and environmental influences. Without this data, we were unable to assess their potential impact on fibromyalgia risk and progression.

Conclusion

This study highlights a significant link between AD and an increased risk of fibromyalgia. Shared neuroinflammatory pathways, including mast cell activation, and overlapping genetic factors, such as polymorphisms in T-helper cells, TLRs, and interferon-related genes, may underlie this association. Vitamin D dysregulation is also a potential contributing factor. These findings support an immunological and neurological interplay between AD and fibromyalgia, though further well-designed cohort studies are needed to confirm these mechanisms and elucidate their biological basis. In clinical practice, this study highlights the importance for clinicians to recognise the heightened risk of fibromyalgia among patients with AD. Early screening and appropriate management of both conditions may significantly enhance patient care and treatment outcomes.