39 patients had typical ColdU confirmed by positive ICT and TempTest® CSTs.

24 patients had atypical ColdU with negative ICT and TempTest® CSTs.

15 healthy controls (HCs) who had no history of pathological reactions associated with cold exposure, and all of them had negative CSTs

ICT was performed following a standard protocol. Briefly, a melting ice cube in thin plastic bag was placed on the volar surface of the patient forearm for 5 min, with macroscopic assessment of the test site 10 min later. TempTest® CSTs were done with TempTest® 4.0 (Courage & Khazaka, Cologne, Germany), which has a single Peltier element (length: 350 mm, width: 2 mm) that provides a continuous temperature gradient from 4°C to 44°C. The use of TempTest® allows for reproducible and standardized cold (and heat) provocation tests and the identification of CTTs. TempTest® CST results were also assessed 10 min after the end of cold exposure.

To compute the blood flow signal, we subtracted slowly time-varying background and frequency components out of the cardiovascular-related range of 0.3-7 Hz. The resulting well-matched, noise-free and intensity-corrected blood flow images are suited for PPG calculation by averaging the intensity pixel values of each frame. The PPG amplitude is proportional to the amount of arterial blood that reaches the visualized skin area and thus characterizes its blood perfusion. It is measured in arbitrary units (AU). We performed photoplethysmographic assessments of the volar forearm of all patients 5 minutes before and 10 minutes after the beginning and end of ice cube application.