Plasma IL‐8 signature correlates with pain and depressive symptomatology in patients with burning mouth syndrome: Results from a pilot study

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Burning mouth syndrome (BMS) is a complex neuropathic orofacial pain (NOP) disorder most commonly associated with bilateral burning, pain or itching sensations within the oral mucosa, with no clear clinical pathology on physical examination.1 According to The International Association for the Study of Pain, BMS is defined as “chronic oral mucosal pain or discomfort that has no identifiable causative lesions and is not caused by any other condition or disease.” The burning episodes commonly occur spontaneously, are usually constant in duration and localised throughout the oral cavity on the tongue, palate, lips and gingiva.2 The symptoms most commonly affect the tip and lateral borders of the tongue.2 Epidemiological data relating to BMS are poor due to a lack of standardised criteria for diagnosis; however, studies estimate BMS prevalence in the general population at approximately 4%, and it usually presents in the 5th‐7th decade of life.3 The condition is seven times more common in females than males.1
Although the precise pathophysiology and aetiology of BMS are unclear, studies have associated the disorder with several mechanisms including primary neuropathic dysfunction,1 central mechanisms involving dopamine receptors4 and psychological factors.5 Importantly, there is a growing body of evidence that supports the hypothesis that BMS is influenced by underlying inflammatory processes, with dysregulated inflammatory profiles detected in patients both systemically and within the oral cavity. Indeed, genetic polymorphisms linked to the pro‐inflammatory cytokine interleukin (IL)‐1β are associated with BMS.6 Furthermore, studies have shown that the inflammatory cytokines IL‐6, IL‐2 and tumour necrosis factor‐alpha (TNF‐α) are elevated in saliva samples from patients with BMS,7 while IL‐6,9 IL‐2 and TNF‐α10 expression are reduced in the serum of patients with BMS.
Pro‐inflammatory cytokines/chemokines are commonly linked with nociceptive signalling and are elevated in neuropathic pain disorders. In terms of orofacial pain, animal studies indicate that IL‐1 signalling mediates allodynia associated with constriction of the buccal branch of the facial nerve,11 and trigeminal nerve injury has been shown to increase IL‐18 expression (an IL‐1 family member) on microglial cells in the trigeminal spinal nucleus caudalis.12 Furthermore, inhibition of the TNF‐receptor prevents orofacial thermal and mechanical neuropathic pain in the orofacial region following carrageenan‐induced inflammation and constriction of the infraorbital nerve.13 The role of cytokines/chemokines in NOP disorders is also supported by human studies. Indeed, RANTES expression is enhanced in degenerated jawbone samples from patients with atypical facial pain and trigeminal neuralgia (TN),14 indicating that pro‐inflammatory chemokines may have a role to play in allodynia associated with NOP.
Patients with TN, facial pain and BMS present with high levels of anxiety and depression.5 Cytokines and chemokines have well‐defined roles in the development of neuropsychiatric disorders, and meta‐analysis of pro‐inflammatory cytokines has confirmed that TNF‐α, IL‐6 and IL‐2 receptors are elevated in serum from patients with major depressive disorder.15 Evidence that cytokine immunotherapy increases the risk of depressive symptomatology supports a link between neuropsychiatric disease and systemic inflammation.16 Alteration in cytokine/chemokine homoeostasis will modulate neural serotonin‐catecholamine signalling to alter patient mood, while cytokine signalling via the hypothalamus‐pituitary‐adrenal axis will contribute to the pathophysiology of depression.17
Considering that inflammation is associated with the pathophysiology of BMS, and that inflammation is closely correlated with pain and depression, we aimed to correlate oral cavity pain and depressive symptomatology with plasma cytokine/chemokine signature in a cohort of patients with BMS. We sought to explore the impact of BMS on the plasma expression profiles of ten individual cytokines/chemokines and relate this plasma signature to clinical symptoms including pain and depression. This study highlights an IL‐8 chemokine signature in plasma from patients with BMS and suggests that subclinical inflammation may be associated with the symptoms of disease.
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