133 Discussion In this study a possible relationship between inflammatory activity and SFN-related symptoms was investigated in patients with sarcoidosis. In our opinion, the data are of special interest due to the fact that inflammatory activity was measured both at baseline and during treatment with FDG-PET, the most sensitive biomarker for inflammatory activity of sarcoidosis at present.18,19 This enabled us to investigate the relationship between the amount of inflammatory activity and SFN-related symptoms as accurately as possible. In concordance with previous studies, treatment with infliximab resulted in a significant decrease of inflammatory activity in patients with sarcoidosis.13,20–22 However, we did not find a relationship between decrease of inflammatory activity and improvement of SFN-related symptoms in patients with sarcoidosis. Therefore, we were not able to find support for our initial hypothesis. Previous studies in pulmonary sarcoidosis demonstrated a relationship between the burden of inflammatory activity present in the lungs at baseline and the amount of pulmonary function improvement after 6 months of treatment with infliximab.22 More recently, in cardiac sarcoidosis, a relationship between the burden of inflammatory activity in the myocardium measured by FDG-PET correlated with left ventricular recovery after treatment with immunosuppressive therapy.23 Based on the fact that the degree of inflammation has decreased significantly in our patients, it is tempting to speculate that SFN-related symptoms can be seen as irreversible damage to the small fibers and not malfunction based on an active inflammatory process. Our findings are not in line with other studies which found a positive relation between anti-TNF-α treatment and reduction of SFN symptoms.20,21 Note that although overall infliximab therapy could not improve SFN-associated symptoms, 50% of patients did show a decrease of more than 3.5 points on the SFNSL questionnaire. Therefore, this group of patients did meet the criteria of minimal important difference with clinical relevance on the SFNSL-score. As mentioned before, ARA290 showed positive effects on inflammation mitigation via innate immune receptors. Patients who showed a decrease of more than 3.5 points on the SFNSL questionnaire, might gain advantage from immune modulation via innate immune receptors rather than reduction of total burden of granulomatous inflammation due to infliximab. There are several limitations in this study. First, the retrospective design resulted in only a small cohort of patients to be studied. We had substantial loss of data due to exceeded time lapse between treatment initiation, date of PET-scan and the date of SFNSL questionnaires. Secondly, we used the SFNSL to assess symptoms but did not accurately diagnose SFN in our patients. Therefore, it could be that we assessed SFN-related symptoms in patients who did not have an actual diagnosis of small fiber neuropathy. Strength of the thesis however is the strong defined group of sarcoidosis patients. As stated before, FDG-PET is highly sensitive for demonstrating inflammatory activity in patients with sarcoidosis. It is actually the first to compare the change in SUVmax with SFN or SFN related symptoms defined by the SFNSL questionnaire. Although our data reveal no association between anti-inflammatory effect of infliximab and SFNrelated symptoms in patients with sarcoidosis, which contradicts previous case-reports and caseseries, further studies are warranted. Given the major negative impact of SFN-related symptoms on the quality of life in patients with sarcoidosis, it is necessary that the possible beneficial effect of antiinflammatory therapy will be addressed in future prospective studies. A large study cohort with clear distribution of SFN phenotypes might give novel insights in effectiveness of anti-TNF-α treatment. 8 139 8
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