154 Measurement of patient-reported outcomes Chapter 4 introduced the new SFNPQ questionnaire and showed the presence of patient reported pain in skin, muscles and joints. The presence of granulomas in organs was compared with the presence of symptoms discussed during consultations with the pulmonologist and neurologist, and with the presence of pain assessed using the SFNPQ. Results showed that minority of symptoms were caused by granulomas in that organ. Furthermore, it showed that less than half of patients who indicate pain on the SFNPQ, also mention this during consultations. Therefore, adding the SFNPQ to the consultation may improve insights in the patients’ symptoms. The SFNPQ results were then stratified by body part and showed especially higher burden of skin pain in the back/abdomen, hands and feet, muscle pain in the thorax, back/abdomen, arms and legs, and joints pain in the feet in patients with sarcoidosis-associated SFN. These results are in accordance with the results presented in Chapter 3 showing a higher burden of symptoms in patients with sarcoidosis and SFN compared to patients with sarcoidosis without SFN. It has been described that patients with sarcoidosis often find themselves trapped in a negative vicious cycle, where depressive thoughts, fatigue, and cognitive impairment contribute to physical deconditioning and a reduced HRQL.27 Our results show a higher burden of fatigue, RLS, pain and cognitive impairment in patients with sarcoidosis and SFN are suggestive for a stronger negative vicious circle of physical deconditioning and probably a deteriorated HRQL for this population. Chapter 7 focused on new phenotypes of pain in the skin measured with the new SFNPQ questionnaire and found an association between continuous length-dependent symptoms and TTT measurements at the feet revealing a possible bias towards length-dependency in current diagnostic criteria.2,28 These criteria were partially based on the Neurodiab criteria29 and the etiology of SFN in that study population was predominantly represented by patients with diabetes and impaired glucose intolerance. Diabetes associated SFN is known to present more often length-dependent.30 This thesis found no correlation between non-length-dependent symptoms and any of the included diagnostic methods, probably because clinical signs as well as IENFD and TTT are dominantly established at distal areas. In addition, symptoms with an intermittent character also showed no association with any of the diagnostic methods. Consequently, non-length dependent and intermittent SFN-related symptoms are prone to false negatives. More awareness for these symptoms should improve diagnosis of SFN. To improve SFN diagnosis, the pathophysiologic mechanisms of intermittent SFNrelated symptoms should be understood first. Depending on these mechanisms, a new diagnostic tool might be developed to quantify intermittent small fiber dysfunction. Moreover, it is important to note that validation of new methods alongside the current diagnostic criteria are vulnerable to adapt a bias towards length-dependent symptoms as shown by the SFNSL which was validated against the TTT, see Figure 4 in Chapter 7. Treatment Improving diagnosis of SFN could improve knowledge about the pathophysiology and could help selecting adequate treatment. To start with treating the underlying disease which results in SFN seems a logical first step.31,32 Treatment for sarcoidosis is not included in standard care protocols and primarily aims to address morbidity, mortality and HRQL.33 SFN significantly affects the HRQL, and as such, may serve as a potential indication for initiating sarcoidosis treatment. Although intravenous immunoglobulin (IVIG) treatment was not effective for idiopathic SFN34 or in our study cohort,35 some case series have shown positive effects of sarcoidosis treatment on SFN related symptoms.5,36 This thesis also identified a mean decrease of 3.5 points on the SFNSL-score in patients with sarcoidosis and SFN-related symptoms after treatment with infliximab, a reduction that exceeded the minimal 10 161 10
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