SENSITIVE SKIN CAN BE SMALL FIBER NEUROPATHY: RESULTS FROM A CASE-CONTROL QUANTITATIVE SENSORY TESTING STUDY F. Huet,1,2 A. Dion,3 A. Batardière,4 A.S. Nedelec,4 F. Le Caër,4, P. Bourgeois,4 E. Brenaut,1,2 and L. Misery1,2 1Department of Dermatology, University Hospital, Brest, France 2Laboratory on Interactions Neurons-Keratinocytes (LINK), University of Western Brittany, Brest, France 3INSERM CIC 1412, University Hospital of Brest, Brest, France 4Complife, Brest, France British Journal of Dermatology. DOI: 10.111/bjd.17082

Prof.Laurent Misery

Introduction : What’s already known? Sensitive skin syndrome (SSS) Defined as the occurrence of unpleasant sensations (itch, pain, burnings, prickling…) in response to stimuli that should not normally cause such sensations Frequent condition Physiopathology remains unclear. Previous studies show SSS could be a small-fiber neuropathy but quantitative sensory testing (QST) is lacking

Objective To determine the presence or absence of tactile sensitivity disorder Using QST: Heat-Pain Threshold (HPT) in subjects with SSS versus controls Secondary objectives To compare the cold (CDT) and vibration (VDT) detection thresholds and the threshold of intermediate pain via the QST, In subjects SSS versus controls The main objective of this study was to evaluate the cutaneous detection threshold of subjects with SSS to heat pain (HP) using the QST and to compare it with thresholds in subjects without SSS to look for an impairment of tactile sensitivity. The secondary objectives were to compare, via the QST, the cold (CDT) and vibration (VDT) detection thresholds and the threshold of intermediate pain in subjects with SSS versus those without SSS.

Characteristics of the study Monocentric case-control (1: 1) study in Brest. Inclusion criteria Exclusion criteria subjects aged between 20 and 60 years subjects with known sensory neuropathy cooperating subjects understanding instructions subjects with pathological alcohol consumption or use of another drug The subjects with SSS were defined by a Sensitive Scale score >50 subjects with cutaneous back injury of the dominant hand or malformation the subjects without SSS were defined by a Sensitive Scale score <20 subjects under topical treatment on the back of the dominant hand Drugs altering nerve or mental functions in progress or taken less than 5 days of medication The inclusion criteria were as follows: subjects aged between 20 and 60 years; cooperating subjects understanding instructions; subjects with written consent, after being informed of the purpose of the study and the protocol; and subjects affiliated with social security. The subjects with SSS were defined by a Sensitive Scale score >50, and the subjects without SSS were defined by a Sensitive Scale score <20. The main exclusion criteria were as follows: subjects with cutaneous back injury of the dominant hand or malformation; subjects with known sensory neuropathy; subjects receiving medical treatment that may, in the opinion of the investigator, interfere with the results; and subjects under topical treatment on the back of the dominant hand.

SENSITIVE SCALE Score>50/100 : SSS Score<20/100: control 2 questionnaires about neuropathic pain The DN4 (Douleurs neuropathiques 4) Neuropathic Pain Symptom Inventary (NPSI)

Quantitative Sensory Testing (QST) Quiet room Heat-Pain (HP) thresholds 25 levels – 34°C to 49°C each stimulus : scale of 0 to 10 3 values: HP 0.5 / HP 5.0 / HP 5.0-0.5

Quantitative Sensory Testing (QST) Quiet room Heat-Pain (HP) thresholds 25 levels – 34°C to 49°C each stimulus : scale of 0 to 10 3 values: HP 0.5 / HP 5.0 / HP 5.0-0.5 Cold (CDT) and vibration (VDT) detection thresholds Algorithm 4, 2, 1 with null stimuli

Demographics characteristics 42 patients included 21 cases Primary endpoint 21 patients analysed 21 control   Case (n=21) Control (n=21) p-value Age Mean+/-SD 39.9 +/- 10.9 39.9 +/- 10.7 1.0000 # Dermatological disease Yes 2 (9.5) 0 (0) 0.4795 * No 19 (90.5) 21 (100) BMI 24.8 +/- 5.2 23.0 +/- 4.9 0.2814 # Dominant hand Left 5 (23.8) 3 (14.3) 0,7266 * Righ 16 (76.2) 18 (85.7) number of hours spent outdoors 1.71 +/- 0.78 1.71 +/- 0.85 Sensitive Scale 57.71 +/- 7.46 2.43 +/- 3.57 <0.0001 # Sensitive scale Consommation OH, tabac et exposition solaire No difference between the two groups except for the Sensitive Scale score * McNemar’s test, # Student’s t-test

Analysis of primary endpoint: heat pain threshold Variable Cases (n=21) Controls(n=21) p-value HP 0.5 Mean+/-SD 14.5 +/- 2.8 17.8 +/- 2.5 0.0007 # Minimum- maximum 9.5 - 19.0 11.3 - 20.6   # Student’s t-test Significant decrease in the threshold for the detection of heat pain in the sensitive skin group

Analysis of secondary criteria Variable   Cases (n=21) Controls (n=21) p-value HP 5.0 Mean+/-SD 20.4 +/- 2.8 23.5 +/- 1.2 0.0014 # Minimum-maximum 15 - 24.0 20.3 – 25.0 HP 5.0-0.5 JND 6.1 +/- 2.8 6.1 +/- 2.1 0.9271 # 1.9 - 13.2 2.9 - 10.8 VDT 4.2 +/- 1.8 4.4 +/- 2.6 0.7528 # 2.1 - 9.8 2.4 - 11.2 CDT -0.39 (-0.54 - -0.27) -0.37 (-0.43 - -0.18) 0.6593 # -0.53 +/- 0.46 -0.45 +/- 0.59 # Student’s t-test Significant decrease of HP 5.0 in sensitive skin group No difference between VDT and CDT

Neuropathic Pain Scales analysis Variable   Cases (n=21) controls (n=21) p-value Questionnaire DN4 total Mean+/-SD 4.52 +/- 1.69 0.05 +/- 0.22 <0.0001 # Questionnaire NPSI total 34.38 +/- 15.14 # Student’s t-test Scores of neuropathic pain were increased in the group sensitive skin

Pain in sensitive skin subjects Decrease in pain threshold HP threshold (HP 0.5) and intermediate pain (HP 5.0) Without changing their rang Correlation with reference data Hyperalgesia ? Neuropathic pain DN 4 and NPSI Saint Martory (2015) : increase of DN4 in sensitive skin patients

Sensitive skin and QST First study : sensitive skin and QST QST in small fiber neuropathy Belongs to the diagnostic criteria Correlation with density of intra-epidermal nerve fibers Difficult comparison between studies Magda et al. (2002) HP in small fiber neuropathy : Se 93% Reproductibility over time Reproductible à 10 semaine.

Sensitive skin = small fiber neuropathy ? Suspicion of nerve damage in sensitive skin Decrease of the HP threshold  Damage of C-fiber C-fiber : neuropathic sensations Buhé et al. (2015)  decrease density of small nerve fiber No damage of VDT and CDT  No interference with beta and delta fiber

Limitations Small sample Women No use of EMG Less common among men Less interest in clinical studies ? No use of EMG Do not burden the protocol Patients with history of neuropathy: excluded No VDT damage : no big fibers reach Test psycho-physique : manque de spé entre atteinte central et periphérique

Conclusions : What does this study add? Scores of neuropathic pain were significantly higher in SSS compared to controls Heat-pain thresholds measured by QST were significantly decreased strongly  suggesting damage to unmyelinated C-fibers. These results are new arguments linking SSS to the spectrum of small fiber neuropathy (SFN). The management of SSS should be dramatically revised at least for the more severe cases

Research Team

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