Immune System Sex Differences May Bridge the Gap Between Sex and Gender in Fibromyalgia

Abstract

The fibromyalgia syndrome (FMS) is characterized by chronic widespread pain, sleep disturbances, fatigue, and cognitive alterations. A limited efficacy of targeted treatment and a high FMS prevalence (2-5% of the adult population) sums up to high morbidity. Although, altered nociception has been explained with the central sensitization hypothesis, which may occur after neuropathy, its molecular mechanism is not understood. The marked female predominance among FMS patients is often attributed to a psychosocial predisposition of the female gender, but here we will focus on sex differences in neurobiological processes, specifically those of the immune system, as various immunological biomarkers are altered in FMS. The activation of innate immune sensors is compatible with a neuropathy or virus-induced autoimmune diseases. Considering sex differences in the immune system and the clustering of FMS with autoimmune diseases, we hypothesize that the female predominance in FMS is due to a neuropathy-induced autoimmune pathophysiology. We invite the scientific community to verify the autoimmune hypothesis for FMS.

The Influence of Pro-inflammatory Cytokines and Genetic Variants in the Development of Fibromyalgia: A Traditional Review

“…The epidemiological profile of fibromyalgia shares some similarities observed in various autoimmune disorders, such as its peak of incidence amongst middle-aged females, "with a female to male ratio oscillating from 1.5:1 to 10:1" [3,13]. Also, it is not unusual to see concomitant autoimmune comorbidities in people diagnosed with fibromyalgia, thereby adding some support to this hypothesis [3]. Several research results about the role and levels of pro-inflammatory cytokines in fibromyalgia have shown controversial results.…”

“…Similarly, the implication of such mediators in multiple conditions associated with chronic pain and inflammation has been evidenced [18]. Despite being "classified as a rheumatic disease, fibromyalgia is mostly treated as a neurological problem" and not as a rheumatic problem [3]. The immune system is just one of several factors that might be involved in the pathophysiology of fibromyalgia.…”

“…One hypothesis suggested that in fibromyalgia patients, inflammatory cytokines could drive disturbances in neural networks during the interaction of the nervous system with immune cells, which eventually could lead to increased central and peripheral sensitization as well as neuroinflammation [ 10 - 12 ]. The epidemiological profile of fibromyalgia shares some similarities observed in various autoimmune disorders, such as its peak of incidence amongst middle-aged females, “with a female to male ratio oscillating from 1.5:1 to 10:1” [ 3 , 13 ]. Also, it is not unusual to see concomitant autoimmune comorbidities in people diagnosed with fibromyalgia, thereby adding some support to this hypothesis [ 3 ].…”

“…Fibromyalgia is defined as widespread pain for more than three months accompanied with multiple symptoms such as fatigue, cognitive dysfunction, unrefreshing sleep, and somatic symptoms. Other manifestations that can be present are dry mouth, dry eyes, musculoskeletal stiffness and tenderness to touch [2][3][4]. Fibromyalgia is associated with multiple comorbidities, particularly with psychiatric and rheumatology disorders [1][2].…”

“…The prevalence of fibromyalgia is around 0.8% to 5% worldwide. In the United States it ranges from 2% to 8%, affecting approximately 5-10 million of the adult population; females represent the majority of the reported cases [ 1 - 3 ]. To date, there is no detailed documentation about significant ethnic variations in fibromyalgia prevalence [ 2 ].…”