59 Discussion This study is the first to investigate a range of non-organ specific symptoms as fatigue, pain, RLS and cognitive impairment specifically related to the presence or absence of SFN in patients with sarcoidosis. We found that the prevalence of fatigue, pain and RLS is higher in patients with sarcoidosis with SFN compared to patients with sarcoidosis without SFN. No difference in prevalence is found for cognitive impairment between patients with sarcoidosis with and without SFN. However, the severity of cognitive impairment is significantly higher in patients with sarcoidosis with SFN compared to patients with sarcoidosis without SFN. Although our cohort of patients with sarcoidosis was dominated by male sex (58%), the group with SFN showed female predominance (56%), while the group without SFN showed male predominance (73%). Almost all autoimmune diseases disproportionately affect women. Several effects have been described on how x-linked genes and female sex hormones are important determinants of granuloma formation.28 The same processes may be involved in increasing the risk of developing sarcoidosisassociated SFN in female individuals. Furthermore, a female predominance of 67% was also observed in patients with idiopathic SFN.29 The bias towards male sex predominance in our cohort may have caused a lower female predominance than in the population with idiopathic SFN. In our cohort of patients with sarcoidosis fatigue is the most prevalent of the investigated symptoms, which is in line with previous studies.2 Interestingly, extreme fatigue defined by a FAS>34 is even more prevalent in patients with sarcoidosis with SFN compared with patients with sarcoidosis without SFN, a new finding further strengthening the previous suggested associations between SFN, pain and fatigue. Among the healthy controls, an elevated FAS-score was also most prevalent, occurring in 15% of this cohort. This is consistent with literature. The cutoff value for a score of up to 21 as normal was previously established based on data from a healthy general population compared to sarcoidosis patients.30 This study showed that 80% of healthy individuals fall below a score of 22, meaning that 20% of healthy individuals are measured as abnormal. In our population, with 15% classified as abnormal, our findings fall within this range. In previous studies, the estimated prevalence of RLS in patients with sarcoidosis varies between 050%.14,15 Our data confirm these numbers and even show a higher prevalence of 67% in patients with sarcoidosis with SFN compared to patients with sarcoidosis without SFN (41%). The important clinical relevance of our finding is the fact that in daily clinical practice an association between SFN and RLS is not known or overlooked. Consequently, RLS will not be investigated or confused with SFN-associated symptoms, while treatment of RLS can be different.31 Therefore, knowledge about the high prevalence of RLS in patients with SFN could be useful in clinical management of patients with SFN. In our study, no difference is found in the prevalence of cognitive impairment in sarcoidosis patients with SFN and without SFN. The prevalence of respectively 46% and 32% is comparable with previous studies addressing cognitive impairment in patients with sarcoidosis.8,9 We did find, however, a significant higher severity of cognitive impairment measured by the CFQ in patients with SFN, comparable with our previous finding regarding extreme fatigue. Once again, this points out that particularly in patients with SFN, clinicians should be aware of the high prevalence and severity of fatigue, pain, RLS and cognitive impairment. Nonspecific health complaints such as fatigue and cognitive impairment are associated with impaired QoL.32 Furthermore, all these aspects might contribute to the negative vicious circle of physical deconditioning and reduced quality of life.2 3 62 3
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