Specific phenotype, comorbidities and unique CLA+ T-cell responses in atopic dermatitis patients with high serum LDHTo the Editor,Lactate dehydrogenase (LDH) is a reliable serum biomarker that correlates with disease severity in non-treated adult patients with atopic dermatitis (AD).1 However, the impact of high or low serum LDH levels on clinical manifestations and immune-mediated mechanisms in patients with AD has not been characterized. We stratified 47 non-treated moderate-to-severe adult AD subjects into LDHhigh (≥ 206 kU/L, n = 24) and LDHlow (< 206 kU/L, n = 23) based on the median levels of serum LDH (Figure 1A) and evaluated whether these two groups were clinically and functionally distinct.Our results showed that serum LDH levels were significantly higher in LDHhigh patients compared to control individuals, while similar levels were found in LDHlow and controls (Figure 1B). Clinically, LDHhigh individuals were younger, exhibited increased disease severity and eosinophil count in blood, as well as elevated house dust mite- (HDM), staphylococcal enterotoxin B (SEB)-specific and total IgE levels in plasma than the LDHlow subgroup (Figure 1C-H). No differences in gender nor pruritus intensity were observed between groups (data not shown). Consistent with previous reports, we observed a positive correlation between serum LDH levels and both EASI and eosinophilia.1,2 Nevertheless, our analysis extended beyond these findings by considering the influence of high or low levels of LDH and demonstrated that these correlations only occurred in LDHhigh and not LDHlow patients (Figure 1I,J). By contrast, serum LDH levels were indirectly correlated with age in the latter, rather than the former group (Figure 1K). Interestingly, we observed a significantly higher prevalence of allergic rhinitis and conjunctivitis, but not asthma nor food allergy, among LDHhigh patients compared to LDHlow(Figure 1L).Next, to assess the effector function of cutaneous immune responses in LDHhigh/low patients, we used a coculture previously stablished by our group,3 made of circulating skin-homing CLA+ or systemic CLA–memory T cells cultured with autologous lesional epidermal cells activated with either HDM extract or SEB. We compared the in vitro response to HDM between groups and found that only CLA+ memory T cells, rather than CLA–, produced significantly higher levels of IL-13, IL-5 and IL-9 in LDHhigh in contrast to LDHlow patients and controls (Figure 2). These results are consistent with the high percentage of AD patients with rhinitis and conjunctivitis, since type 2 cytokines contribute to the development of allergic comorbidities. Additionally, these findings also align with previous data from our group reporting high LDH levels in patients with IL-9 production.4 The amount of IL-4, IL-31, IL-22, IL-17A and IFN-γ produced by HDM-activated CLA+/Epi cocultures was similar among AD groups. Interestingly, no differences in cytokine production were found when using SEB to activate the cocultures in the same cohort of patients, except for CLA+T-cell-derived IL-31 levels (Figure S1).This is the first report showing that serum LDH levels distinguish patients with AD in terms of clinical features and in vitro T-cell responses. In conclusion, we consider that assessing serum LDH levels may be beneficial to stratify patients for therapeutic selection, given the complex heterogeneity of AD and the recently suggested capacity of LDH to predict treatment response in Asian populations.5,6WORD COUNT: 514